J a v a d J a m s h i d i

F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s , D e c e m b e r 2 0 1 5

Cancer Genetics

Sess ion 4Medical Genetics

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What is Cancer?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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Cancer ClassificationCarcinoma

Originate 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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Is it due to Genetic Factors?

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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Family Studies

The frequency with which other family members develop the same cancer can provide evidence for a genetic contribution.

For a woman who has a first-degree relative with breast cancer, the risk is between 1.5 and 3 times the risk for the general population.

In gastric cancer, first degree relatives have a 2-3 fold increased risk compared with the general population

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Epidemiological Studies

Breast cancer

Women who have borne children have a lower riskThe younger the age has her first pregnancy, the lower riskThe later the age at menarche, the lower breast cancer riskVaries greatly between different populations

Gastric cancer

People from lower socioeconomic groups have an increased riskSalts and preservatives, nitrates, are possible carcinogensShows variations in incidence in different populationsHelicobacter pylori infection, increases the risk by five to six fold

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Classes of Cancer Genes

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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Oncogenes

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

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Chronic Myeloid Leukemia

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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Tumor Suppressor Genes

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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RetinoblastomaThe 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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Retinoblastoma

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'Two-Hit' Hypothesis

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TP53The 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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Multistage Process of Colorectal Cancer Development

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Breast CancerMost 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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Prostate CancerThe 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)

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What did you learn?

Cancer Definition

Genes involved in Cancer

Different mechanisms