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308 Cards in this Set
- Front
- Back
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Cancer strikes 1 in __ people, accounts for __% of all death and __% of medical care cost in developed country
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3, 20%, 10%
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disease process characterized by uncontrolled cellular proliferation leading to mass or tumor
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neoplasia
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growth no longer controlled and tumor capable of progression by invading neighboring tissues
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malignant
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tumor arisen in mesenychmal tissue- bone, muscle, connective tissue, nervous system
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sarcomas
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tumor originating in epithelial tissue like cells lining intestine, bronchi, or mammary ducts
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carcinomas
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2 examples of hematopoietic and lymphoid malignant neoplasms?
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leukemia, lymphoma
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tumors are classified by ___, ___, ___, and __
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site, tissue type, histology, degree of malignancy
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class of normal cellular protein-coding genes that promote growth and survival of cells
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proto-oncogene
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mutant allele of a proto-oncogene, facilitate malignant transformation by stimulating proliferation or inhibiting apoptosis, encode proteins such as proteins in cell signaling pathways for cell proliferation, TF's that control expression of growth-promoting genes, inhibitors of programmed cell death machinery
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oncogene
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2 types of tumor suppressor genes
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gatekeepers or caretakers
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types of genes that control cell growth, block tumor development by regulating transition of cells through checkpoints in cell cycle or promote programmed cell death and control cell division and survival
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gatekeeper tumor suppressor genes
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A LOF mutation of a gatekeeper gene leads to ___
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uncontrolled cell accumulation
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these genes protect integrity of genome, encode proteins responsible for detecting and repairing mutations, proteins involved in normal chromosome disjunction during mitosis, components of programmed cell death machinery
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caretaker tumor suppressor genes
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LOF mutation of caretaker genes leads to ___
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mutations in oncogenes and gatekeeper genes which initiate and promote cancer
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4 types of mutations which initiate cancer
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1) GOF mutations turning on oncogenes or proto-oncogenes 2) ectopic and heterochronic mutations of proto-oncogenes 3) chromosome translocations causing misexpression of genes or create chimeric genes encoding proteins with novel function properties 4) LOF of both alleles or a dominant negative mutation of one allele of tumor suppressor genes
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Describe the ways that a tumor progresses
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accumulating addition genetic damage through mutations or epigenetic silencting of caretaker genes; leads to altered expression of genes promoting vascularization and spread of tumor through local invasion and distant mets
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3 activated oncogenes causing increased risk of cancer
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RET, MET, RAS
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2 gatekeeper tumor suppressor genes increasing risk of cancer when mutated
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RB1, TP53
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2 caretaker tumor suppressor genes increasing risk of cancer when mutated
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MSH2, MLH1
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apoptotic gene leading increasing risk of cancer when mutated
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FAS
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2 antiapoptotic genes increasing risk of cancer when mutated
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BCL2, telomerase
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development of cancer
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oncogenesis
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having an initial cancer-causing mutation inherited through germline
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hereditary cancer syndrome
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mutations occurring in single somatic cell and then dividing and proceeding to develop into cancer
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sporadic
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miRNA associated with cancer
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oncomirs
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small non-coding RNA molecule which functions in transcriptional and post-transcriptional regulation of gene expression
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miRNA
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a condition with 100x overexpression of miRNA miR-21, causes highly malignant form of brain cancer
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glioblastoma multiforme
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Overexpression of some miRNA's can ___ expression of tumor-suppressor genes and LOF may allow ___ of oncogenes they regulate
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suppress, overexpression
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genetically unstable cells that give rise to multiple sublineages of varying degrees of malignancy, each carrying different but overlapping mutations
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cancer stem cells
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Hereditary cancers are only seen in about __% of cancer cases?
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5%
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a regulatory mutation in growth factor genes leads to ____
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increased expression
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a structural mutation in growth factor receptors and signal-transducing proteins leads to ___
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allows autonomy of expression
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translocation, retroviral insertion, and gene amplification of TF's leads to ___
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overexpression
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regulatory mutations, translocations, and retroviral insertions of oncomirs leads to ___ and ___
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overexpression and down-regulation of tumor suppressor genes
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deletion and inactivating mutations of oncomirs leads to ___ and ___
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loss of expression and up-regulates oncogenes
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At the cellular level, oncogenes have a __ effect meaning ____
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dominant, it only takes one mutant allele to initiate change in phenotype of a cell from normal to malignant
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a cell, group of cells, or organism that is descended from and genetically identical to a single common ancestor
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clonal
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chromosome translocations (3) involved in Burkitt lymphoma
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t(8;14)(q24;q32) and t(8;22)(q24;q11) and t(2;8)(q11;q24)
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Which protooncogene is affected by the t(8;22)(q24;q11) translocation in Burkitt Lymphoma?
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MYC
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chromosome translocation in CML and AML?
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t(9;22)(q24;q11)- Philadelphia chromosome
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Proto-oncogene affected in CML and AML?
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BCR-ABL
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Chromosome translocation in acute promyelocytic leukemia?
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t(15;17)(q22;q11)
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proto-oncogene involved in acute promyelocytic leukemia?
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RARA-PML
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Chromosome translocation in chronic lymphocytic leukemia?
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t(11;14)(q13;q32)
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proto-oncogene involved in chronic lymphyocytic leukemia?
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BCL1
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Chromosome translocation in follicular lymphoma?
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t(14;18)(q32;q21)
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proto-oncogene involved in follicular lymphoma?
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BCL2
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What gene is found in bladder carcinoma cell lines and others and when mutated is signaled continuously even without bound GTP?
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RAS
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RAS genes encode one of a large family of ___ proteins
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G
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How do G proteins work?
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serve as molecular "on-off" switches that activate or inhibit downstream molecules when bound to GTP but then terminate effect when bound GTP is cleaved to guanosine diphosphate by intrinsic GTPase enzymatic activity
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Sometimes a proto-oncogene is activated by chromosome mutation, usually through translocation in sporadic ___ and ___ and sometimes ___
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leukemias, lymphomas, sarcomas
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Sometimes translocation breakpoints within introns of 2 genes, fusing them into one abnormal gene encoding ____ protein with ___ properties
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chimeric, novel oncogenic
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philadelphia chromosome is a translocation between chromosomes __ and __, moves proto-oncogene ___ from normal position on chromosome __ to breakpoint cluster region gene ___ on ___
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9, 22, ABL, 9q, BCR, 22q
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drug to inihibit extra activity of BCR/ ABL in philadelphia chromosome
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Imatinib
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B-cell tumor of jaw mostly in what country
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Africa
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proto-oncogene translocated from 8q24 to position distal to to Ig heavy-chain locus at 14q32
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MYC
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overexpression of antiapoptotic proteins in lymphocyte lineages could result in vast expansion of lymphocyte populations contributing to ____
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lymphoma
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__gene is activated by t(14;18) translocation placing gene under strong promoter and enhancer of Ig heavy chain gene at 14q32, leads to B-cell lymphoma
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BCL2
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The protein encoded by BCL2 is a mitochondrial inner membrane protein with powerful ___ effects in B-cells
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antiapoptotic
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reverse transcriptase required to synthesize hexamer repeat, TTTAG as component of telomeres at end of chromosomes
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telomerase
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what is the need for telomerase
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DNA polymerase can only add nucleotides to 3' end of DNA and can't complete synthesis all the way to 3' end of template strand
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As cells differentiate, telomerase activity declines in all somatic tissue except in ____
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highly proliferative cells of tissues that must undergo self-renewal such as bone marrow
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When do telomeres shorten and what is the result of this?
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telomeres shorten with each cell division causing chromosome damage causing cells to stop dividing and enter G0 of cell cycle and cells will undergo apoptosis
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How is telomerase activity in some tumors changed?
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persists in many tumors and permits them to proliferate indefinitely like MYC gene
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In tumor suppressor genes, need to lose function in ___ allele(s) for these genes to stop working
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2
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BRCA1 and 2 are what kind of genes?
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caretaker genes
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DCC is a ___type of gene and causes ___ type of cancer
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gatekeeper, colorectal cancer
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VHL, RB1, TP53, DCC, and VHL are all what kind of gene?
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gatekeepers
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What type of genes are MLH1 and MSH2
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mismatch repair genes
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A second hit causing cancer is generally one of two types of mutations, including __ and ___?
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somatic mutation or LOF without mutation like transcriptional silencing (with DNA methylation causing a closed chromatin configuration and loss of accessibiltiy of DNA to TF's)
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___% of cases of RB are of heritable form, __% have unilateral RB and most are bilateral with early onset
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40%, 15%
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__% of RB cases are sporadic, unilateral, and early childhood onset
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60%
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APC mutations are associated with what condition mostly?
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FAP
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PTEN mutations are associated with what two cancers?
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glioblastoma, prostate cancer
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RB1 is associated with what 3 cancers?
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Retinoblastoma, Breast cancer, osteosarcoma
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TP53 is associated with what 2 cancers the most?
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colorectal and breast
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3 chromosomes associated with frequent LOH in breast carcinomas?
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8q, 16q, 17q (includes BRCA1)
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3 chromosomes associated with frequent LOH in small-cell lung carcinomas?
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3p, 10q, 4q, 5q, 13q, and 17p
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loss of heterozygosity may occur by ___, ___, or ___
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interstitial deletion, mitotic recombination or nondisjunction
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___ is the most common mutational mechanism by which the function of normal RB1 allele is disrupted in hets
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LOH
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loss of heterozygosity is evidence of what kind of gene?
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tumor-suppressor
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What kind of cancers are infants with heritable RB who survive childhood cancers more at risk for, especially if they received radiation?
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osteogenic sarcomas, fibrosarcomas, melanomas
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In RB1, only see eye tumors in what time frame of life?
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childhood
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Loss of RB1 gene deprives cells of an important ___ and allows uncontrolled proliferation
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mitotic checkpoint
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Loss of P53 function causes ____
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allows cells with damaged DNA to survive and divide, propagating potentially oncogenic mutations
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Affected members in ___% of families with LFS carry a TP53 mutation
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70%
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LFS is a what type of gene?
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gatekeeper tumor suppressor
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Normal NF1 gene functions in regulation of _______
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cell division and neural tissue
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NF1 is what type of gene
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tumor suppressor
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__% of all women in N. America and W. Europe will develop breast cancer in their lifetimes
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9%
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Familial hereditary cancers in HBOC have what 4 characteristics?
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1) multiple affected individuals in family 2) earlier age at onset 3) frequent bilateral disease 4) ovarian and prostate cancer and others
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BRCA1 and 2 account for ___% and __ of AD familial breast cancer
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50%, 1/3
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BRCA2 accounts for ___% of all male breast cancer
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10-20%
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__% risk of breast cancer by 70yo in women hets for BRCA1 or 2
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45-80%
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Colon cancer is _____% of all cancers
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15%
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Besides FAP, what other syndrome is caused by mutations in the APC gene?
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Gardner syndrome
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condition causing adenomatous polyps with malignancy, osteomas of jaw and desmoid
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Gardner syndrome
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APC is what type of gene?
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gatekeeper tumor-suppressor
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__% of colon cancer is caused by HNPCC
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2-4%
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Males with HNPCC mutations have a 90% LT risk for developing___ cancer and females have a 70 and40% risk for ____ cancer as well as a 10-20% chance of ___, ___, and ___ cancers
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colon, endometrial, UT, biliary, ovary
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3 most common genes responsible for HNPCC
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MLH1, MSH2, MSH6
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HNPCC genes are what type of gene?
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caretaker tumor-suppressor
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microsatellite instability is called ___ phenotype and occurs at 2x orders of magnitude higher frequency in cells lacking both copies of a ___ gene
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replication error positive (RER+), mismatch repair
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Mutations secondary to repeat instability occurring in tumor suppressor genes?
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APC and TGFBR2
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Heterozygotes of AR chromosome instability syndromes with caretaker gene mutations are at increased risk for ____
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malignant neoplasia
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Heterozygotes of Ataxia Telangectasia have 2x increased risk of ___ cancer before 50yo in females
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breast
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Heterozygotes of Fanconi Anemia can have mutations in what gene that would increase their risk of cancers?
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BRCA2
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2 genes commonly mutated in sporadic cancers
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TP53 and RB1
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Genes mutated in sporadic colon cancers? (6)
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MLH1, MSH2, APC, RAS, TP53, SMAD4
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12% of sporadic colon cancers have a ___ phenotype, but most do not.
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RER+ phenotype
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How does one determine the chance a woman might have a BRCA1/2 mutation?
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family history, age at onset, penetrance, HER2 status (usually triple neg in hereditary cancers)
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When the probability of a woman having a BRCA1/2 mutation is 1 in ____ or greater, recommend testing
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10
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When the probability of a man having a BRCA1/2 mutation is ____, recommend testing
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recommend testing for all males with breast cancer
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How does one determine the chance a woman might have HNPCC?
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age at onset, location of tumor in colon, presence of a second tumor or history of cancer, family history of colon cancer or other cancers, RER+ phenotype of tumor
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rare AD condition with massive lymphadenopathy and splenomegaly and development of autoimmune phenomena like antibody-mediated thrombocytopenia and hemolytic anemias like B-cell and Hodgkin lymphomas, Fas receptor and Fas-ligand problems
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autoimmune lymphoproliferative syndrome
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phenomenon in which there are many additional copies of a segment of genome present in cell; common in many cancers like neuroblastoma, SCC of head/neck, colon cancer, malignant glioblastomas of brain, readily detected by CGH
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gene amplification
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very small accessory chromosomes seen on CGH when there is gene amplification
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double minutes
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areas that don't band normally on CGH and contain multiple, amplified copies of a particular DNA segment
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homogeneously staining region
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Amplified regions known to include extra copies of which proto-oncogenes stimulate cell growth, block apoptosis, or both (3)
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MYC, RAS, epithelial growth factor receptor
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amplification of MyCN protooncogene encoding N-Myc is important clinical indicator of prognosis of ____; amplified more in advanced stage and less in early-stage
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neuroblastoma
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Amplification of genes encoding target of chemo has been implicated as mechanism for development of ___ in patients previously treated with chemo
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drug resistance
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___% of cancer is due to environment
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75%
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what is the multistep process of cancer?
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normal epithelium->adenoma->late adenoma->early cancer->late cancer
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What does the Gail model not incorporate?
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cancers besides breast cancer, SDR's, paternal Hx, age at Dx in relatives
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What model incorporates age, age at first live birth, age at menarche, # FDR with breast cancer, Br Bx yes/no, # of Br Bx's, presence of atypical hyperplasia, race
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Gail model
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which model provides an absolute LT risk of breast cancer to age 90 and a 5-year risk of Br Ca
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Gail model
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Women who have ___ or ___ are not used in the Gail Model
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LCIS or DCIS
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What is the only risk factor taken into account in the Claus table and how is this calculated?
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family history; need to find appropriate table for each family and this can be inaccurate
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prior probability testing like BRCAPro, CAgene, MMRPro, and PANCpro offer what?
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determine chance an individual will test positive for specific testing; prior probability models
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adenosis, apocrine changes, duct ectasia, mild hyperplasia yield ___ risk for cancer
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no increased risk
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hyperplasia- moderate or florid, sclerosing adenosis yield __ risk for cancer
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slightly increased (proliferative with atypia)
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atypical ductal or lobular hyperplasia yield ___ risk for cancer
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moderately increased, especially with family history of breast cancer
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DCIS or LCIS provide ___ risk of cancer
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high risk
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What type of DCIS has a higher chance of becoming invasive
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comedo
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Subsequent invasive cancers after LCIS are usually ___, __, __
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ductal, multicentric, and bilateral
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risk factors for breast cancer
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aging, nulliparity, fam Hx, HRT use, early menarche, >2 alcoholic bevs/week, late menopause
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protective factors for breast cancer
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>4+ hrs exercise/wk, breastfeeding, maintaining ideal body weight (esp. after menopause), having children <30yo
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___% of breast and ovarian cancer are hereditary
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5-10%
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70% of ovarian cancers are associated with ___ mutations, 20% ___, 2% ___, 8% other single gene disorders
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BRCA1, BRCA 2, HNPCC
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incidence of BRCA1/2 mutations in AJ pop
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1/40
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How do PARP inhibitors work as treatment for breast cancer?
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block PARP (enzyme in DNA base excision repair), cell then dies and spares normal cells; esp. helpful in triple neg breast cancers
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gene responsible for tumor suppressing, on chrom 17, protein has role in genomic stability, increases risk of breast cancer, second primary breast cancer, ovarian cancer, colon/pancreatic/male breast cancers
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BRCA1
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gene responsible for tumor suppressing, on chrom 13, protein has role in genomic stability, increases risk of breast cancer in males and females, ovarian cancer, prostate cancer, pancreatic cancer, melanoma,
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BRCA2
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Mastectomy reduces risk of breast cancer by ___%
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>90%
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oophorectomy reduces risk of breast cancer by ___% in pre-menopausal women and ovarian cancer risk by ___%
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>50% and 80-90%
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This drug reduces risk for second breast cancer in BRCA+ women, but also increases risk of uterine cancer
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Tamoxifen
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this drug reduces risk for second breast cancer without increasing risk of uterine cancer
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Raloxifene/AI's
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condition increasing risk of sarcoma, brain cancer, breast cancer, leukemia, childhood adrenocortical tumors, choroid plexus tumors
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Li Fraumeni Syndrome
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condition causing macrocephaly, trichilemmomas (hair follicle tumors), papillomatous papules, Lhermitte-duclose disease with cerebellar dysplastic gangliocytoma (benign brain tumor), breast/thyroid/uterine/thyroid cancers, hamartomatous intestinal polyps, lipomas, fibromas, uterine fibroids, fibrocystic disease of breast, autistic spectrum disorder
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Cowden
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Thyroid cancers in Cowden are usually what type?
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follicular
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2/3 to 3/4 of Cowden cases have ___ in addition to thyroid cancers
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goiters
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50% of women with Cowdens have ___ in addition to uterine/endometrial cancers
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fibroids
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condition causing macrocephaly, hamartomatous intestinal polyps, speckled penis, proximal muscle myopathy, joint hyperextensibility, pectus, scoliosis, DD, hemangiomatosis, lipomatosis, increased cancer risk
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Bannayan-Riley-Ruvacalba
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condition causing connective tissue nevi, disproportionate overgrowth, lipomas or absence of fat, vascular malformations, facial phenotype
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Proteus syndrome
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CHEK2 1100delC, PALB2, ATM, and BRIP1 are all genes that are low penetrance but do increase risk of ___ cancer
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breast
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risk factors for colorectal cancer
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aging, personal history of CRC or adenomas, high fat/low fiber diet, IBD with UC or Crohen's, family history of CRC, hereditary colon cancer syndromes
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General US pop risk of CRC is ___%
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5-6%
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___% of CRC is sporadic, __% familial, __% FAP, __% HNPCC ___% rare CRC syndromes
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65-85%, 10-30%, 1%, 5%, 0.1%
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condition with AD inheritance, APC tumor suppressor gene on chromosome 5q, 100% risk of cancer if untreated polyposis, elevated risk of upper GI/osteoma/thyroid/brain/hepatoblastoma cancers, CHRPE, 100's to 1000's of colorectal adenomatous polyps
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FAP
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variant of FAP, features of FAP as well as desmoid tumors, osteomas, supernumerary teeth, CHRPE, soft tissue skin tumors
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Gardner's Syndrome
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variant of FAP with later onset (50yo), >20 but <100 polyps, no CHRPE, upper GI lesions, mutations at 5' and 3' ends of APC gene
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attenuated FAP
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Clinical management for FAP
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annual colonoscopy, colectomy, annual upper endoscopy, chemoprevention, monitoring for desmoids, genetic testing in family
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found mutation in AJ population, associated with increased LT CRC risk, phenotype indistinguishable from sporadic CRC
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APC mutation I1307K
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AR inheritance, colon polyposis syndrome, >15 polyps and <1000's, onset in 50's, polyps adenomatous,"", increase in risk of duodenal polyps and duodenal cancer, ovarian, bladder and skin cancer (sebaceous gland tumors)
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MYH-associated polyposis (MAP)
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Y165C and G382D
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common MYH-associated polyposis gene mutations
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what is the difference between "HNPCC" and "Lynch Syndrome"
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HNPCC are families that meet Amsterdam criteria and Lynch syndrome are families that actually have a known germline MMR gene mutation
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What is Amsterdam criteria for HNPCC?
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3+ relatives with verified CRC in family, one of relatives an FDR, 2+ generations, 1 CRC by age 50yo, FAP excluded
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Revised Bethesda guidelines determine if tumors should be tested for IHC/MSI; describe these guideline
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CRC in pt>50yo, synchronous or metachronous CRC's or other tumors associated with HNPCC, CRC with high MSI or DX'd in <60yo patient, CRC or tumor associated with HNPCC Dx'd<50yo in at least 1 FDR, CRC or tumor associated with HNPCC dx'd at any age in 2 FDR or SDR
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LT risk of cancer with Lynch Syndrome?
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70%
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Tumor is usually on the ____ part of the colon and ____ type in Lynch Syndrome
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R side proximal, signet ring or mucinous or tumor-infiltrating medullary pattern
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LS increases risk of what type of extracolonic cancers?
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endometrial, stomach, ovarian, pancreas, ureter/renal pelvis, biliary tract
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condition with same risks as Lynch Syndrome and additionally sebaceous gland adenomas and keratocanthomas, mostly MSH2 mutations but also MLH1
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Muir-Torret Syndrome
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condition with same risks as Lynch Syndrome and additionally glioblastoma
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Turcot syndrome
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If a tumor has MSI high, is positive (present) for all IHC proteins, and a BRAF mutation, then tumor is likely due to ____
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sporadic
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If tumor has MSI high, any IHC - and neg for BRAF mutation, then tumor is likely due to ____
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germline mutation
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Homozygous ___ mutations in this mismatch repair gene leads to severe phenotype of Lynch Syndrome with early onset CRC, duodenal cancer, leukemia, lymphoma, childhoood brain tumors, CAL spots
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PMS2
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Surveillance for HNPCC
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colonoscopy beginning at 20-25yo and repeat 1-2 yrs, transvaginal U/S and endometrial Bx annually beginning at 25-35yo, urinalysis annually, upper GI EGD beginning 30-35yo and repeat every 1-2 yrs
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prophylactic surgery options for HNPCC
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subtotal colectomy, hysterectomy, oophorectomy, polypectomy, proctocolectomy
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__% of families that meet Amsterdam criteria will not have detectable mutation or MSI in colon tumor
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45%
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HNPCC families without MMR gene mutation or phenotype of Lynch with MSS, intact IHC, do not show other HNPCC associated cancers, may show later agge of onset, lower rates of second tumors, unknown genes involved
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familial colon cancer syndrome X
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describe the 2 subtypes of Turcot's syndrome
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APC mutations associated with medulloblastomas and MMR mutations associated with glioblastomas
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GI hamartomomas, dark pigmentation around mouth, fingers, toes which may fade after puberty, freckling on lips across vermilion border; increased risk of small bowel, ovary, sex-cord tumors (Sertoli cell tumor), pancreatic cancer, stomach, colon, breast, ovarian, uterine, and lung cancers, <100 hamartomatous GI polyps and most common in small intestine, adenomatous polyps sometimes, polyps in respiratory tract and UT, obstruction, intussusceptions, abdominal pain, GI bleeding
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Peutz-Jegher
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gene mutation in Peutz-Jegher
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STK11
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multiple juvenile GI polyps from stomach to rectum, hamartomatous polyps, 3-5 up to 100 juvenile polyps are Dx, presents with bleeding, Dx'd at ANY age, risk for colon, stomach and small bowel cancer; AD inheritance
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Juvenile polyposis syndrome
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Mutations in what genes cause juvenile polyposis syndrome?
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BMPR1A and SMAD4
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Some people who have SMAD4 mutations have juvenile polyposis syndrome and ___
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HHT
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Mutation causing hereditary diffuse gastric cancer/lobular breast cancer?
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CDH1
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hundreds of foci in diffuse gastric carcinoma, signet ring carcinomas, onset 40yo, higher risk for lobular breast cancer, AD inheritance, CDH1 gene mutation
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hereditary diffuse gastric cancer/lobular breast cancer
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clinical management of hereditary diffuse gastric cancer/lobular breast cancer
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prophylactic total gastrectomy at about 20yo, endoscopic screening for those who decline surgery or those too young
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adenocarcinoma derived from renal tubule epithelium; hereditary forms usually multifocal, bilat and early age of onset, sporadic often solitary lesions
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renal cell carcinoma
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70-80% of RCC's are ____ type, 10-15% are ___, 3-5% are ____, and 1% are ___
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clear cell, chromophile-papillary, chromophobe, collecting duct
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condition with AD inheritance, 24.7yo mean age of onset, hemangioblastomas in cerebellum, retina and spine, endolymphatic sac tumors, pancreatic cysts and hemangioblastomas, pheos, RCC's multiple renal cysts, bilateral papillary cystadenomas of broad ligament or epididymis, liver hemangiomas, pulmonary hemangiomas
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VHL
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___% of VHL is de novo and ___% sensitive in testing
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20%, 100%
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Type 1 VHL patients are at ___ risk of hemangioblastoma, __ risk of RCC, ___ risk of pheos
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high, high, low
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Type 2A VHL patients are at __ risk of hemangioblastioma, __ risk of RCC, __ risk of pheos
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high, low, high
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Type 2B VHL patients are at ___ risk of hemangioblastoma, ___ risk of RCC, __ risk of pheos
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high, high, high
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Type 2C VHL patients are ___ risk of hemangioblastomas, ___ risk of RCC, __ risk of pheos
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no, no, high
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Screening for VHL
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full MRI of brain/spine at 11yo, opthalmological exam <5yo, every 6 mo's 15-30yo, annual or semi-annual contrast CT or MRI in childhood, biochemical screening starting at 5yo
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bilateral, multifocal papillary renal cancer, 50-70yo onset, kidney only affected organ, d/t activation of proto-oncogene c-MET
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hereditary papillary renal carcinoma
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RCC (chromophobe, hybrid chromophobe/oncocytomas, clear cell type occasionally, often multiple and bilateral), fibrofolliculomas, pulmonary cysts and spontaneous pneumothoraces, BHD gene mutation, protein product is folliculin, AD inheritance,
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Birt Hogg Dube
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cutaneous leiomyomata, fibroids, renal tumors- type II papillary, collecting duct cancer, occasional clear cell, AD inheritance, FH gene mutation
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hereditary leiomyomatosis and Renal Cell Ca
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multiple CAL, axillary freckling and macrocephaly, NO lisch nodules/neurofibromas/CNS tumors, Noonan-like dysmorphology, DD
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NF1
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multiple cutaneous and spinal schwannomas, tumors of peripheral nerve sheath, not vestibular schwannomas, AD inheritance, mutations in NF2/SMARCB1/IGLC1/INI1
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schwannomatosis
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2 types, type 1 is classic form with angiomyolipomas, renal cysts, RCC, tubers in brain and type 2 is milder with increased risk of psychiatric disease and polycystic kidneys; Skin: hypomelanotic macules, facial angiofibroma, shagren patch, ungual fibromata. CNS: subependymal glial nodules, cortical tubers, giant cell astrocytoma, seizures. Renal: angiomyolipomas, epithelial cysts, <1% malignant transformation. Heart: cardiac rhabdomyomas, regress in infancy without intervention. Lymph: lymphangiomatosis (TSC2, women 20-40yo)Eye: hamartomas or achromic patches.
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tuberous sclerosis (TSC)
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85-90% of thyroid cancers are ____ type
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well-differentiated
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85.90% of well-differentiated thyroid cancer is ___ type and 10% is ____
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papillary, follicular
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75% of thyroid cancer is ___ (inheritance)
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sporadic
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__% of thyroid cancer is hereditary
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10%
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20% of hereditary thyroid cancer is ____ and ___; 2% is ___
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MEN2A and 2B, FMTC
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Bilateral MTC and familial pattern seen in what condition?
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FMTC
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Bilateral MTC, familial pattern, pheos and hyperparathyroidism seen in what condition?
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MEN2A
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95% of people with MEN2 have what subtype?
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2A
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bilateral MTC in early childhood, familial and not, pheos, mucosal neuromas, intestinal ganglioneuromas, marfanoid habitus, medullated corneal nerve fibers, problems with colonic function seen in what condition?
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MEN2B
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MEN2B medical management
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prophylactic thyroid surgery in first 6 months of life, if level 2 mutations then thyroidectomy before 5yo and if level 1, thyroidectomy before 10yo
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Any patient with medullary thyroid carcinoma should be tested for ____
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RET mutations
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Subtype of MEN with 100% risk of MTC, 50% risk of pheos, and 10-20% risk of hyperparathyroidism
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2
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Thyroid cancer syndrome where 95% of cases have parathyroid tumors and onset 20-25yrs, pituitary tumors, endocrine tumors of gastro-entero-pancreatic tract, adrenocortical tumors, AD inheritance, facial angiofibroma, collagenoma, CAL, lipomas
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MEN1
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tumors that arise in neuroendocrine tissue
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paragangliomas
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tumors that hypersecrete catecholamines, can be found in abdomen or thorax, usually termed extra adrenal pheo
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sympathetic paraganglioma
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tumors that are usually in head/neck region, biochemically silent, glomus tumors, chemodectomas, carotid body tumors, nonchomaffin tumors, named by location
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parasympathetic paraganglioma
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rare tumors most frequently arising from the adrenal medulla, hypersecrete catecholamines causing episodic sweating/BP elevations/anxiety/palpations/weight loss
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pheos
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When someone is <35yo with PH/FPGL Dx (one instance), family history or syndromic presentation, extra-adrenal or multiple tumors, and/or bilateral adrenal tumors or a second instance of malignant tumor, what condition/gene would you consider?
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VHL
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If there is a family history or syndromic presentation, a Dx of PH/FPGL, <35yo diagnosis, bilateral adrenal tumors, what gene would you consider?
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RET
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If there is a family history or syndromic presentation, extra-adrenal or multiple tumors, Dx of PH/FPGL, 2nd instance of PH/FPGL <35yo diagnosis in family, apparently sporadic presentation, 2nd instance of bilateral adrenal tumors in family, and malignant tumor or 2nd instance of malignant tumor, what genes to consider?
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SDHB,SDHB
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condition with SDHD gene mutations, pheos or PGL, head and neck paragangliomas, AD inheritance, maternal genomic imprinting
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PGL1
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condition with HPGL, rare, SHDC gene, AD inheritance
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PGL3
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condition with SDHB gene mutation, HPGL, sPGL (extra-adrenal pheos), adrenal pheos, 50% of pheos are malignant, higher risk for malignant paragangliomas, mean age of Dx 30's-50's, AD without maternal imprinting
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PGL4
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having pheos, gastric leiomyosarcoma, pulmonary chondroma and adrenal adenomas is called the ___
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carney triad
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which conditions have the carney triad?
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familial PGl and gastric stromal sarcoma, VHL, MEN2, NF1
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90% of melanoma is inherited how?
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nonfamilial
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20-40% of hereditary melanomas have ___ gene mutations and <3% are due to ___ gene mutations
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CDKN2A, CDK4
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Candidates for genetic counseling with melanomas?
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individuals with >3 primary invasive melanomas, 2+ cases of melanoma in a family and/or pancreatic cancer among FDR or SDR in same lineage
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3 genes that play a smaller role in melanoma?
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p14^ARF, CDK4, and MC1R
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ABCD warning signs for skin cancers?
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Asymmetry, Border, Color, Diameter
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Screening for people with risk factors for melanoma?
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derm exams starting at 10yo, heightened at puberty and pregnancy, body photography for moles, monthly skin checks, sun protective behaviors, pancreatic screening, annual MRI-MRCP and endoscopic U/S
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A person's risk of melanoma with a CDKN2A mutation varies by ____
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location (higher in Australia, lower in Europe for instance)
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Pancreatic risk in a family with CDKN2A mutations can be as high as ___%
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25%
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a family with CDKN2A mutations is said to have what syndrome?
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Familial Malignant Melanoma Mole Syndrome
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condition with high risk for basal cell carcinomas, jaw keratyocysts, PTCH mutations, AD inheritance, pits on palms of hands or soles of feet, macrocephally, medulloblastoma in childhood, CL/P, bifid ribs or wedge-shaped spinal bones, extra fingers/toes, eye problems, cardiac or ovarian fibromas, abdominal cysts
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NBCCS (Gorlin)
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condition with extreme photosensitivity, defective endonuclease activity and defective nucleotide excision repair, cell hypersensitivity to UV induced DNA damage pyrimidine dimers, premature skin again, many skin cancers often by 8yo, all sun exposure avoided, AR inheritance
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XP
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condition with immmunodeficiency, progressive cerebellar ataxia (1-4yo), wheelchair bound by 10yo, telangiectasis of conjunctivae, enhanced sensitivity to radiation, increased risk of leukemia/lymphoma, AR inheritance
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ataxia telangectasia
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Which test is more sensitive than genetic testing for AT?
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immunoblotting
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What protein is elevated in individuals with AT?
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AFP
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condition with short stature, changes in skin pigmentation, radial malformations of thumbs/forearms, progressive bone marrow failure with thrombocytopenia and leukopenia by 8yo, myelodysplastic syndrome or AML, solid tumors of head/neck/esophagus/cervix/liver, hypersensitivity to mitomycin C or diepoxybutane
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Fanconi Anemia
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Dx testing for FA
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chromosome breakage/DEB testing
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The majority of people with FA have what subtype?
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FANCA (66%)
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Family history of Wilms Tumor is present in __% of cases
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1-2
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most common renal tumor in children
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Wilms tumor
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2 familial genes causing increased incidence of bilateral Wilms tumor and earlier age of onset
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FWT1/2
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overgrowth syndromes causing Wilms tumor
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BWS and isolated hemihypertrophy
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non-overgrowth syndromes causing Wilms Tumor
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WAGR, Denys-Drash
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50% of BWS is due ____, 20% due to ____, 10% due to ____, 2-7% due to _____
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DMR2 loss of methylation, paternal UPD, CDKN1C mutation, DMR1 gain of methylation
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related tumors with an RB1 mutation
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pinealoma or primitive neuroectrodermal tumors of the brain, osteosarcomas, soft tissue sarcomas, melanoma
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cancer seen in a tumor with trisomy 8
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myeloid neoplasia
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cancer seen when there are deletions of 5q21-22
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colon cancer
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cancer seen when there are deletions of 11p13 or 11p15
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Wilms tumor
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cancer seen when there are deletions of 13q14.2
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retinoblastoma
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mutation in which gene causes Bannayan-Riley-Ruvalcaba?
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PTEN
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FLCN / BHD genes are associated with what condition?
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Birt-Hogg-Dube
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myxomas of heart and skin, hyperpigmentation of skin (lentiginosis), endocrine overactivity, embolic strokes, heart failure, fever, joint pain, SOB, diastolic rumble and tumor polyp, endocrine tumors and Cushing syndrome
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Carney Complex (formerly NAME and LAMB syndromes)
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PRKAR1A gene is associated with what condition?
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Carney complex/NAME/LAMB syndromes
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rare bone tumor at base of skull, in vertebrae or tailbone, become symptomatic in second decade or life or later, grow slowly and ambiguous symptoms
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chordoma (familial)
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leukocytosis, splenomegaly, fatigue and malaise, additional chromosomal abnormalities in the tumor, aenmia, thrombocytosis and thrombocytopenia, fever, bone lesions; blast crisis in acute leukemia, BCR-ABL oncogene
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CML
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BCR-ABL oncogene is associated with what condition?
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CML
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nail dystrophy, lacey reticular skin hyperpigmentation or generalized hyperpigmentation muscosal leukoplakia, BM failure frequent, short stature, premature loss of hair and teeth, hyperhidrosis of palms and soles, telangiectasiae, hair tufts with hyperkeratotic plugs, keratinized basal cell papillomas, pulmonary fibrosis, esophageal stricture, urethral stricture, liver dz, GI abnormalities, increased predisposition to SCC of head and neck and AML. AD type more mild.
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dyskeratosis congenita
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inheritance of dyskeratosis congenita
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XLR (majority) and AD if in TERC gene or AR if in NOP10/NOLA3, TINF2 genes
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hyperkeratosis of esophagus by teens leading to esophageal cancer
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familial esophageal cancer, Howel-Evans Syndrome
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May see parathyroid hyperplasia, parathyroid adenomas, cystic parathyroid adenomas, elevated parathyroid hormone levels (renal stones, hypercalcemia, osteoporosis, pancreatitis). Parathyroid malignancy is in about 15% of neoplastic glands so aggressive management advicsed. Parathyroid adenomas seen in males>females at about 32yo, fibrous maxillary or mandibular tumors resemble ossifying or cementifying fibromas (30%), hamartomas, multiple cysts or polycystic renal disease, renal cortical adenomas, renal failure, benign uterine disease
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familial hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis
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gene associated with familial hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis
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HRPT2
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multiple GI stromal tumors, cutaneous hyperpigmentation with multiple nevi and/or urticaria pigmentosum, dysphagia, upper GI pain, GI bleeding, hyperpigmentation, GI autonomic nerve tumors with hyperplasia and severe diverticulosis, GISTS malignant, cancers in stomach mostly then small intestine and esophagus/colon/rectum
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GIST and Multiple GI autonomic nerve tumors
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C-KIT, PDFFRA genes associated with what condition?
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GISTs (hereditary)
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gene associated with Gorlin
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PTCH
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poorly differentiated adenocarcinoma infiltrating into stomach wall causing thickening of wall without forming distinct mass, signet ring carcinoma or isolated cell type carcinoma also seen in this condition, women have risk of lobular breast cancer too
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hereditary diffuse gastric cancer
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CDH1 is gene associated with what condition
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CDH1
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cutaneous leiomyomata on trunk/extremities/face increasing in size and number with age, uterine leiomyomata (fibroids), and/or single renal tumor causing back pain, hematuria, leydig cells of testis/breast/bladder cancers
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hereditary leiomyomatosis and RCC
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FH (fumarate hydratase) gene mutation is associated with what condition?
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hereditary leiomyomatosis and RCC
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CDKN2A, CDK4, and CMM4, CMM1 are all genes associated with what condition?
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hereditary multiple myeloma
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condition with elevated risk of multiple melanomas on upper trunk and limbs, pancreatic cancer, astrocytomas, breast cancer, and ocular melanoma
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hereditary multiple myeloma
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increased risk of congenital central hypoventilation syndrome, neuroblastoma, ganglioneuroblastoma, ganglioneuroma, increased urinary catecholamines, bilateral adrenal or multifocal primary tumor
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hereditary neuroblastoma
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PHOX2B gene associated with what condition?
|
hereditary neuroblastoma
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PALLD is a gene associated with what condition?
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hereditary pancreatic cancer
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MET is a gene associated with what condition?
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hereditary papillary RCC
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paragangliomas in head/neck and pheos, extra-adrenal malignant transformations, associated with SDHD/SDHC/SDHB/SHDAF2 genes
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hereditary paraganglioma/Pheo Syndrome
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which genes exhibit parent of origin effect in hereditary paraganglioma/pheo syndrome?
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SDHFA2 and SDHD
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SDHFA2 and SDHD exhibit more paragangliomas and pheos when inherited from which parent?
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paternal
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HPC, HPC2, PCAP, HPCX, CAPB, HPC20, MSR1, BRCA1/2, NBS1 (9% of men), CHEK2, KLF6 are associated with what condition?
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hereditary prostate cancer
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condition with increased risk of colorectal cancer, multiple primary breast cancers, stomach/small bowel/pancreas/kidney/endometrium/ovaries cancers, middle adulthood onset, mismatch repair gene problem
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HNPCC/Lynch
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increased risk of hodgkin's lymphoma, CLL, NHL, breast, ovarian, kidney, cervical and brain cancers
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familial Hodgkin lymphoma
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hamartomatous polyps in GI tract; most benign but malignant transformation can occur, BMPR1A and SMAD4 mutations; named for type of polyps
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Juvenile polyposis
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BMPR1A and SMAD4 associated with which condition?
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juvenile polyposis
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sarcoma of bone, cartile, soft tissue, early onset breast cancer, spine or brain tumor, childhood adrenocortical tumors, Wilms tumor, malignant phyllodes tumor
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LFS
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P53 and CHEK2 mutations are associated with what condition?
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LFS
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embryonal rhabdomyosarcoma, Wilms tumor, leukemias, severe IUGR<microcephaly, anomalies of eyes, dysmorphism, DD, seizures, congenital heart anomalies, GU anomalies, Dandy-Walker complex, quadriplegia, suspect sarcomas and hematological abnormalities
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mosaic variegated aneuploidy
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BUB1B associated with what condition?
|
mosaic variegated aneuploidy
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familial multiple myeloma seen associated with what gene?
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BRCA2
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benign nerve tumors like schwannomas, meningiomas, ependymonas, astrocytoma, bilateral acoustic schwannoma, HL, tinnitus, balance problems, cataracts, mononeuropathy, CAL, 36yo average age of death
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NF2
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Growth deficiency, microcephaly, sloping forehead, prominent midface, retrognathia, recurrent sinopulmonary infections, decline in cognition after 1yr with mild ID, POF frequent, hyper and hypopigmented irregular spots, immunodeficiency (IgA, agammaglobulinemia, T-cell defects), chromosomal inversions and translocations involving immunoglobulin loci (esp chrom 7 and 14). Increased risk of chromosome breaks and multiradials formed among nonhomologous chroms and exposure to ionizing radiation or radiomimetic agents increases this further. 35% develop malignancy- usually B-cell lymphomas or hematopoetic malignancy. maybe also glioma, rhabdomyosarcoma, medulloblastoma, prostate and breast cancer, GI lymphoma, gastric and colorectal cancer
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Nijmegen Breakage syndrome or AT variant or Berlin Breakage Syndrome
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NBS1 gene mutation associated with what condition
|
Nijmegen Breakage syndrome
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Multiple primary RT's in affected individuals (ex: brain, kidney) at very young age. Also see renal and extrarenal malignant AT/RTs, choroid plexus carcinoma, medulloblastoma, central PNET, meningioma, myoepithelioma, familial schwannomatosis
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rhabdoid predisposition syndrome
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SNF5 associated with what condition
|
rhabdoid predisposition syndrome
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sun-sensitive rash (100%) btw 3-6mo as erythema, swelling, blistering on cheeks and face then spread to buttocks and extremities sparing chest/back/abdomen then leads to poikiloderma (telangiectasias, reticulated pigmentation, punctate dermal atrophy) through adulthood. may also have small stature, skeletal dysplasia, radial ray defects, sparse scalp hair, sparse brows or lashes, cataracts, osteosarcoma, skin cancer
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rothmund-thomson syndrome
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RECQL4 mutation associated with what condition?
|
Rothmund-thomson syndrome
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undescended testes, inguinal hernias, hypospadias, reduced fertility, semen abnormalities, bilateral testicular germ cell tumors. 2-3x increased risk of sporadic and familial TGCT. Bilateral cancers 3.5times more frequent in familial than sporadic.
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testicular germ cell tumor, familial
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TGCT1 on X-chromosome associated with what condition?
|
testicular germ cell tumor, familial
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nephrogenic rests, benign foci of embryonal kidney cells persisting abnormally into postnatal life, additional intralobar rests associated with WAGR and D-D, perilobar rests with BWS. Wilms tumor has potential for local and distant spread. Usually presents as abdominal mass (42-47mo's unilat, 30-33 mo's bilat) causing abdominal pain, fever, anemia, hematuria, HTN (25-30%), 5-10% have bilateral or multicentric tumors
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Wilms tumors
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WT1 associated with what conditions?
|
WAGR, Denys-Drash, Frasier, GU anomalies
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XPA, XPC, ERCC2-6 and 8, POLH, DDB2 associated with what condition?
|
Xeroderma pigmentosum
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ATM is gene involved in what condition?
|
ATM
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