1. Javad Jamshidi Fasa University of Medical Sciences, November 2015 Session 9 Medical Genetics Cancer Genetics

2. 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

3. 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

4. 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

5. 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 5

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 6

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 The viral oncogenes are copies of normal cellular genes, proto-oncogenes 7

8. 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 ) 8

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10. 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 10

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13. 13 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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15. 15 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

16. 16 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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18. 18 'Two-Hit' Hypothesis

19. 19 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

20. 20 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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23. 23 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

24. 24 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

25. 25 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)