Javad Jamshidi Fasa University of Medical Sciences, December 2015 Cancer Genetics Session 4 Medical Genetics

Uncontrolled growth of cells Not all tumors are cancerous Six characteristics of cancer cells: Self-sufficiency in growth signaling Insensitivity to anti-growth signals Evasion of apoptosis Enabling of a limitless replicative potential Induction and sustainment of angiogenesis Metastasis and invasion of tissue 2

Carcinoma Originate in epithelial origin, Most common,80-90 percent of all cancer Sarcoma Originates in supportive and connective tissues Myeloma Originates in the plasma cells of bone marrow Leukemia Cancers of the bone marrow (the site of blood cell production) Lymphoma Originate in glands or nodes of the lymphatic system 3

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 4

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 5

Breast cancer Women who have borne children have a lower risk The younger the age has her first pregnancy, the lower risk The later the age at menarche, the lower breast cancer risk Varies greatly between different populations Gastric cancer People from lower socioeconomic groups have an increased risk Salts and preservatives, nitrates, are possible carcinogens Shows variations in incidence in different populations Helicobacter pylori infection, increases the risk by five to six fold 6

Oncogenes Their normal activity promotes cell proliferation. Act as the accelerator Tumor suppressor genes Products act to limit normal cell proliferation Act as the break DNA Repair Genes 7

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 8

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 9

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11 These are genes whose function is to keep the behavior of cells under control. Restraining or suppressing inappropriate cell division Maintaining the integrity of the genome Ensuring that incorrigibly deviant cells are sentenced to death by apoptosis Loss of function mutations

12 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 either Sporadically, the so-called nonhereditary form Familial, the so-called hereditary form, Inherited in an autosomal dominant manner.

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14 'Two-Hit' Hypothesis

15 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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17 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

18 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)

19 Cancer Definition Genes involved in Cancer Different mechanisms