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17 Cards in this Set

  • Front
  • Back
Most INHERITED cancers are due to changes in __
Tumor Supressor genes
Origin of mutations in oncogenes
Most are somatic
Constitutional mutations are generally not found.
Exceptions: 1. MET
2. RET (table 12.3 in book is wrong)
Mutations are up-regulating. They cause expression in a cell where it is not supposed to be. Do not see frameshift, non sense, or deletions.
Mutations are missense, amplification, translocation, and promoter alteration. All causing gain of function.
These genes are not more prone to mutation
oncogenes: inherited missense mutations
MET (7q31) – AD papillary renal cancer- activating mutations that cause the receptor to function as an active tyrosine kinase in absence of ligand.
Second (and third or fourth) hits are needed for the cells to become clonal
oncogenes: inherited missense mutations
MEN2:
AD - RET gene (10q11.2) – Multiple Endocrine Neoplasia 2 – specific recurrent mutations cause the spectrum of familial medullary thyroid cancer, MEN2A and MEN2B
RET encodes a tyrosine kinase receptor that binds glial cell growth factor and neurturin (loss of fx implicated in Hirchsprung)

Thyroidectomy is performed as young as age 6 months in patients with certain RET mutations
Oncogene amplification
Increased copy number of an oncogene

Example: N-myc in neuroblastoma

Her-2 Neu/cERB2 and c myc occurs in breast cancer (somatic)

May be detected by comparative genomic hybridization/microarray
oncogene translocation
Chromosomal Rearrangements causing oncogenes to be abnormally expressed.
Tumor specific
Commonly seen in hematopoetic cancers
Often involve a transcription factor
In Burkitt’s Lymphoma the c-myc oncogene on chrom 8 is translocated to 2,14,or 22 at the site of the immunoglobin loci.
Causes expression of c-myc
Chromosomal abnormalities and cancer: Aneuploidy
Trisomy 21 – occasionally see myeloid proliferation which may develop into leukemia; 20 fold increase over the population in leukemia (acute megakaryocytic leukemia risk is 400X)

Mosaic Turner syndrome – increased risk for gonadoblastoma (correlates with presence of Y chromosome)

Klinefelter (XXY) males have increased risk of breast cancer.
chromosomal abnormalities: structural defects
WAGR (wilm’s tumor, aniridia, genital abnormalities, mental retardation contiguous gene syndrome on 11p13

WT1 gene deletion causes Wilm’s tumor

Children with the deletion are screened for renal tumors with ultrasound every 4 months until age 5.

Retinoblastoma – some are caused by deletion of the 13q14 region – (first hit)
epistatic changes and cancer
In imprinting disorders there are no changes in DNA sequence
Beckwith-Weideman Syndrome – pre and post natal excessive growth, macroglossia, organomegaly, omphalocele, hernia and hemihyperplasia are variable features
several growth regulatory genes with genomic imprinting are implicated with the etiology of BWS.
Two distinct imprinting domains at 11p15:
telomeric domain containing H19 and IGF2
centromeric domain including KCNQ1, KCNQ1OT1, and CDKN1C.
The types of tumors observed in children with telomeric defects (mainly Wilms tumors) were different from those observed in cases with aberrations limited to the centromeric domain (rhabdomyosarcoma and gonadoblastoma).
Tumor suppressor genes
Retinoblastoma, Von Hippel Lindau, Neurofibromatosis.
BRCA 1 and 2, Li Fraumeni
Familial Retinoblastoma
20% of patients with Bilateral RB have a family history – so 80% are de novo
Penetrance is 90%
Gene encodes a cell cycle protein that normally inhibits G1 to S phase by recruiting histone deacetylases to inhibit transcription of genes required for S phase
Tumore suppressor gene: two hit hypothesis
Dominant inheritance at the organism but recessive at the cell level (dominance and recessiveness are properties of phenotypes not of mutations or genes)
In familial (inherited) cases one inherits one mutation in a tumor suppressor gene and acquires the loss of a second normal copy.
Second hit leads to tumorigenesis.
There are many mechanisms for loss of function – the second hit.
malignancies reported in Beckwith-Weidemann Syndrome
Wilms Tumor, Hepatoblastoma
testing for Rb inherited Rb mutations
Testing is different for unilateral vs bilateral cases

Bilateral – check Rb gene from blood
Unilateral – check Rb gene in blood and tumor
second malingancies in Rb cases
Mesenchymal tumors are the most common childhood cancer (400x risk) – Osteosarcoma, fibrosarcoma, melanoma
68% incidence of second primary malignancy to age 50.
Radiation therapy may increase risk of malignancy.
Von Hippel Lindau
Major cause of death is Renal cell carcinoma (clear cell)
Mortality also caused by cerebellar and spinal hemangioblastomas
Retinal angiomas – often the presenting sign of VHL
Occurrence of pheo are highly dependent on mutation location.
Pancreatic cancer and endolymphatic sac tumor also occur.
Tumor supressor genes

NF-1
17q11

Neurofibromatosis