Oncology And Microarray Week 12

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(neoplasm) is a growth of tissue that

exceeds and is not coordinated with normal

tissue

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A tumor

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epithelial solid tumor

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Carcinoma

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bone, cartilage, muscle, blood vessels, fat solid tumor

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sarcoma

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solid tumor in multiple cell types

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Teratocarcinomas

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Movement of dislodged malignant tumor cells from the original (primary) site to other locations

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metastasis

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Hematological malignancies

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Tumors arising from white blood cells

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Neoplastic disease of blood forming tissue where large numbers of WBCs populate the bone marrow and peripheral blood

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leukemia

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Neoplasm of lymphocytes that forms discrete tissue masses

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lymphoma

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Histologically and clinically different disease than

all other types of lymphoma

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Hodgkin’s Disease

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Arise from terminally differentiated B cells and are classified in a separate category

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Plasma cell neoplasms

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normally promote cell division

or cell survival

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proto-oncogene

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usually a gain of function and dominant

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Oncogene mutations

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genes normally arrest cell division. a loss

of function and recessive

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tumor suppressor genes

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Not expressed in normal cells

translocations, point mutations, polymorphisms in tumor suppressor or oncogenes

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Tumor-specific markers

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Molecular characteristics of the type of tissue from which a tumor arose Presence of DNA or RNA from these targets in abnormal amounts or locations is used to detect and monitor antigens, gene rearrangements. Although useful, these markers are expressed by normal cells so they do not always prove the presence of cancer

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Tissue- specific markers

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HER2-expressing tumors are sensitive to

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herceptin, a monoclonal antibody therapy

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encodes one of a family of human epidermal growth-factor receptors

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The HER2/neu gene

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This gene is mutated or amplified in several types of cancer cells. Over expression has been correlated with poor clinical outcome. sensitive

to tyrosine kinase inhibitors, detected by IHC

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EGFR, epidermal growth factor receptors

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G- protein genes in mammals produce four

similar proteins, mutations occur in many

types of cancers

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ras

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most common oncogene mutations in cancer

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K-ras

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Mutations on K-ras

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throw the Ras protein into a permanently active state

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a family of childhood neoplasms

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Ewing Sarcoma, EWS

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Group of tumors arising from primitive

neuroectodermal tissue (PNET)

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Ewing Sarcoma, EWS

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Rare type of cancer of the muscle, fat, fibrous

tissue, blood vessels, and other supporting tissue

Accounts for 8% - 10% of all sacomas

Occurs most frequently in young adults

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Synovial sarcoma

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Most common soft-tissue sarcoma of childhood

Accounts for 10% of all solid tumors in children

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Rhabdomyosarcoma

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worse prognosis of Rhabdomyosarcoma

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Alveolar rhabdomyosarcoma (ARMS)

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is mutated in half of all types of cancer.

Loss of _________ function is an indicator of poor

prognosis in colon, lung, breast, and other

cancers.

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TP53

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Neurological disease that causes predisposition

to cancer. Occurs in 1/40,000 live births

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Ataxia telangiectasia

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Caused by mutations in the ATM (A-T mutated)

gene on 11q22

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Ataxia telangiectasia

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Carriers for the autosomal recessive mutations

in ATM are at increased risk for developing

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leukemia, lymohoma and other cancers

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Direct sequencing of ATM gene and SSCP

Function test for repair of dsbreaks induced

by irradiation may also be performed

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Ataxia telangiectasia diagnosis

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% of breast cancers result from inherited gene

mutations

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5

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Women with a mutation in BRCA1 have a

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60% – 80% lifetime risk of breast or ovarian cancer

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Men carrying mutations, especially in BRCA2, have a

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100-fold increased risk of breast, colon,

and prostate cancer

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BRCA1 and BRCA2 are

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tumor suppressor genes

encoding proteins that participate in DNA repair.

Front 36

Genetic condition involved in abnormal

growth of blood vessels in organs, especially

those that are rich in blood vessels caused by mutations in a gene. predisposition for renal

cell carcinoma and other cancers

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von hippel lindau

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avian myelocytomatosis viral-related

oncogene

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v-myc

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is an oncogene that is counteracted by

the tumor suppressor gene,

neurofibromatosis type 1 (NF1

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n-myc

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is example of how different mutations in

the same gene result in different diseases

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RET gene

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found in thyroid papillary carcinomas, found in inherited multiple endocrine neoplasia (MEN) syndromes, Hirschsprung’s disease, a rare congenital disorder resulting in colonic obstruction

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RET gene

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most common form of hereditary colon cancer.

associated with mutations in genes

encoding components of the mismatch repar

(MMR) system, most frequently MLH1 and MSH2

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Lynch Syndrome or Hereditary nonpolyposis

colorectal carcinoma (HNPCC)

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short tandem repeats) are sensitive to errors during DNA replication.

These errors are normally corrected by the

mismatch repair system (MMR)

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microsatellites

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MLH1 ,MSH2, and several other genes

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Components of the MMR system

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the production of new alleles from unrepaired replication errors

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Microsatellite instability

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85 – 90% HNPCC tumors have

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MSI

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MSI is analyzed by

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assessing stability of at least five microsatellite loci

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two-hit hypothesis

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Loss of heterozygosity reveals the loss of the good allele at a locus, which uncovers the homologous locus with a recessive mutation

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Inherited tumor suppressor gene mutations

are

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recessive for the malignant phenotype

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Tumor suppressor gene mutations are

dominant with respect to

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increased risk of malignancy

Front 50

Loss of a linked heterozygous STR implicates

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a concurrent loss of one gene allele

Front 51

The completion of GR on only one of the two

immunoglobulin heavy chain gene alleles is

referred to as

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allelic exclusion

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A leukemia or lymphoma is ________ with regard to Ig or TCR rearranged genes

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monoclonal

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When over _______ of cells make the same gene

rearrangement, the cell population is referred to as monoclonal

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1%

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Monoclonal populations are detected by (Southern Blot)

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rearranged bands

unique to the tumor cell

population

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Monoclonal populations are detected by (PCR)

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sharp bands unique to the tumor cell population

Front 56

Targeting clonality of gene rearrangements

may only be applied to tumors arising from

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lymphocytes

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Translocations and other abnormalities in

chromosome structure and number are

detected by

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FISH

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qPCR may be used to quantify

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tumor load during patient monitoring

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one chromosome has split and the DNA is rearranged by the insertion of a piece from another chromosome or a different part of the same chromosome

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A breakpoint

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10% - 20% of breakpoints fall into

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a cluster closer to the BCL2 gene in the minor cluster region (MCR)

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chimeric genevbetween the breakpoint cluster region (BCR) gene on chromosome 22 and the Abelson leukemia virus (ABL) gene on chromosome 9

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Philadelphia chromosome

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t(9;22) diseases?

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chronic myelogenous leukemia and acute lymphoblastic leukemia

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use a standard curve of transcripts of known copy numbers diluted into normal RNA

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For RT-qPCR

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A collection of miniaturized test sites
(microarrays) arranged on a solid substrate
that permits many tests to be performed at
the same time in order to achieve higher
throughput and speed

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biochip

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Microarray technology evolved from

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southern blotting

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Studies determining protein binding site occupancy throughout the genome, employing chip-on-chip technology

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Chromatin immunoprecipitation

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Looking for single nucleotide polymorphism in the genome of populations.

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SNP detection arrays

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Orderly arrangement of samples on microarray. distance?

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200 microns

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cystic fibrosis carrier results

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eSensor

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how many bases long immobilized on a solid
surface by robotics?

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500-5000

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angiotensin-converting enzyme (ACE) indicative of

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coronary artery disease

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D/D deletion/ deletion

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high failure rate for placement of stent