Javad Jamshidi

Fasa University of Medical Sciences, November 2015

Session 9Medical Genetics

Cancer Genetics

Uncontrolled growth of cells

Not all tumors are cancerous

Six characteristics of cancer cells:

Self-sufficiency in growth signalingInsensitivity to anti-growth signalsEvasion of apoptosisEnabling of a limitless replicative potentialInduction and sustainment of angiogenesisMetastasis and invasion of tissue

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CarcinomaOriginate in epithelial origin, Most common ,80-90 percent of all cancer

SarcomaOriginates in supportive and connective tissues

MyelomaOriginates in the plasma cells of bone marrow

LeukemiaCancers of the bone marrow (the site of blood cell production)

LymphomaOriginate in glands or nodes of the lymphatic system

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Small proportion is predisposed by inherited germline mutations behaving as mendelian traits

For many cancers, environmental factors are etiologically more important than heredity

Cancer is a genetic disease of somatic cells

End result of an accumulation of both inherited and somatic mutations in cell growth related genes

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The detail in cancer genetics can be overwhelming

Every tumor is individual

There are so many different genes that acquire mutations in one or another tumor, and they interact in complex ways

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OncogenesTheir normal activity promotes cell proliferation.Act as the accelerator

Tumor suppressor genesProducts act to limit normal cell proliferationAct as the break

DNA Repair Genes

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Gain of function mutations - excessively or inappropriately active.

A single mutant allele may affect the behavior of a cell.

The nonmutant versions are properly called proto-oncogenes

The viral oncogenes are copies of normal cellular genes, proto-oncogenes

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Secreted growth factors (e.g. SIS )

Cell surface receptors (e.g. ERBB and FMS)

Components of intracellular signal transduction systems (e.g. the RAS family and ABLl )

DNA-binding nuclear proteins, including transcription factors (e.g. MYC and JUN)

Components of the network of cyclins, cyclin-dependent kinases, and their activators and inhibitors (e.g. CCNDl and MDM2 )

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In 1960, in Philadelphia an abnormal chromosome in white blood cells from patients with chronic myeloid leukemia (CML) was described.

Philadelphia, or Phi, was chromosome 22 with t(9;22)(q34;qll) translocation. seen in 90% of those with CML

Resulting in a chimeric transcript derived from both the c-ABL (70%) and the BCR genes

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An unusual form of neoplasia seen in children in Africa is a lymphoma that involves the jaw

90% of affected have a translocation of the c-MYC oncogene from the long arm of chromosome 8 on to heavy (H) chain immunoglobulin on chromosome 14.

MYC comes under the influence of the regulatory sequences of the immunoglobulin gene and is overexpressed 10-fold or more

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These are genes whose function is to keep the behavior of cells under control.

Restraining or suppressing inappropriate cell divisionMaintaining the integrity of the genomeEnsuring that incorrigibly deviant cells are sentenced to death by apoptosis

Loss of function mutations

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The paradigm for our understanding of the biology of tumor suppressor genes

Retinoblastoma (Rb) is a relatively rare, highly malignant, childhood cancer of the developing retinal cells of the eye

Rb can occur eitherSporadically, the so-called nonhereditary formFamilial, the so-called hereditary form,

Inherited in an autosomal dominant manner.

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'Two-Hit' Hypothesis

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The TP53 gene is the most frequently mutated of all the known cancer genes.

Seen in some 20% to 25% of breast and more than 50% of bladder, colon, and lung cancers

It functions as a checkpoint control site in the cell cycle at G1 before the S phase

An inherited or germline mutation of TP53, Li-Fraumeni syndrome, an autosomal dominant trait

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Some cancer cells express high levels of telomerase, so that cell viability is maintained.

Most metastases contain telomerase-positive cells, suggesting that telomerase is required to sustain such growth.

However, cancer cells generally have shorter telomeres than the normal cells surrounding them

Telomere length is therefore almost certainly a key concept in many cancers

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Cowden disease is autosomal dominant but very variable

Gastrointestinal polyps are found in about half of the cases and are generally benign adenomas.

High incidence (50%) of breast cancer in females, and papillary thyroid carcinoma in about 7% of the patients

Mutations in the tumor suppressor PTEN gene on chromosome lOq23, encoding a tyrosine phosphatase

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Most common women cancer, 1/12 in west, between age of 40 and 55

1 in 3 develop metastatic disease. Some 15% to 20% have family history

About 40% to 50% of families with early-onset autosomal dominant breast cancer have a mutation in the BRCA1, 60% to 85% lifetime risk of breast cancer.

BRCA2 gene account for 30% to 40% of families with early-onset autosomal dominant breast cancer

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The most common cancer affecting men

lifetime risk of 10% of developing the disease and a 3% chance of dying from

About 15% have a first-degree male relative with prostate cancer

9% of all prostate cancers and up to 40% of early onset prostate cancers, hereditary prostate cancer-l and -2 (HPCl and HPC2)