1. Chapter 11 Cancer Genetics

2. Cell responses to environmental signals

3. A familial colon cancer pedigree

4. Tumors genetic and environmental causes → transformation of cell → tumorigenesis malignant neoplasm/benign neoplasm classification of tumors Carcinomas from epithelial tissue Sarcomas from connective tissue Lymphomas from lymphatic tissue Gliomas from glial cells Leukemias from hematopoietic cells

5. Stages of Tumor Development

6. Invasiveness and Metastasis of Cancer Cells

7. Causes of cancer Genetic causes somatic mutations: not inherited germline mutation: inherited Environmental causes a composite of both genetics and environment, with interaction between the two components

8. A general process of signal transduction pathway

9. Signal Transduction and Cancer

10. Inherited Cancer Gene vs. Somatically Altered Gene A genetic form of RB (retinoblastoma) mutation 50% chance of genetic transmission, bilateral several tumors A sporadic form of RB mutation no genetic transmission, unilateral two independent mutations in the same retinoblast → only one tumors understanding the nature of inheritically mutated genes ⇔ understanding the nature of somatically mutated genes

11. Two hit model of carcinogenesis

12. Tumor Suppressor Genes

13. RB1 gene a tumor-suppressing gene, 13q14 one mutant RB1 gene/one normal RB1 gene → no tumors the second hit of mutation on the other RB1 gene → tumors RB protein unphosphorylated pRb binding to E2F transcriptional complex (inactivation): blocking cell cycle before S-phase phosphorylation of RB protein by CDK → release from E2F complex → resuming cell cycle Tumor suppressor genes are recessive at the cellular level, but dominant at the individual level

14. Cell Cycle Regulation of Rb and E2F p16

15. Cell Cycle Regulation of Rb and E2F

16. Loss of Heterozygosity Loss of heterozygosity

17. Oncogenes and Their Roles in Cancer by study of retrovirus transmission SIS, ERBB, RAS, MYC, JUN, FOS by transfection experiments RAS by mapping in tumors Abl

18. Key Features of Tumor Suppressor Genes and Oncogenes

19. DNA Repair Genes and Chromosome Integrity Defective DNA repair → genomic instability → tumorigenesis Types of genomic instability defective repair of double-stranded breaks (familial breast cancer) faulty DNA mismatch repair (hereditary nonpolyposis colorectal cancer) impaired nucleotide excision repair (Xeroderma pigmentosum) aneuploidy: extra copies of oncogene or lost of tumor suppressor genes

20. DNA Repair Genes

21. How to map tumor suppressor genes By linkage mapping in families: defining a region By analysis of chromosomal losses associated with revealed tumor suppressor genes By detection of mutations in DNA from patients An example : Neurofibromatosis Type 1 (NF1) linkage analysis (within 30-40 mb) → translocation mapping (within 5 mb) → pulling out candidate genes → identification of mutations in patient → analysis of NF1 gene (neurofibromin) in databases (GTPase- activating protein, a tumor suppressor)

22. Neurofibromatosis Type 1 (NF1)

23. Localization of the NF1 gene

24. TP53 Gene Identification of TP53 by analysis of chromosomal losses and deletion → 17p Functions of p53 protein phosphorylated p53 binding to the promoter of p21 (a CDK inhibitor) → cell cycle arrest for DNA repairing phosphorylated p53 binding to the promoter of gene involved in apoptosis → cell death mutation of p53 → escape from DNA repair and apoptosis Li-Franmeni syndrome (LFS, AD) by germline mutation of TP53 or CHK2 (p53 kinase) developing multiple primary tumors at early ages a causative role of p53

25. p53 in Cancer

26. Cell Cycle Regulation of p53 Mouse double minute 2 homolog (MDM2, E3 ubiquitin-protein ligase) CHK2

27. Familial Adenomatous Polyposis (APC) Gene Familial adenomatous polyposis (FAP) (or adenomatous polyposis coli, APC) multiple adenomas → becoming malignant colon cancer APC gene a tumor suppressor gene, mutated in over 85% of sporadic colon cancer linkage analysis, overlapping deletions → 5q Need multi-hits for tumor progression to the metastatic stage (need at least 7 mutations of APC, KRAS, SMAD4, TP50, etc) Function of APC protein down-regulate β-catenin → affecting the Wnt signaling pathway → controlling cellular proliferation down-regulate β-catenin → affecting cell adhesion mediated by E-cadherin → normal cell adhesion controlling microtubule activity

28. Multiple Mutations in Colon Carcinomas

29.  -Catenin in the Wnt Signaling Pathway

30. Hereditary Nonpolyposis Colon Cancer Genes (HNPCC) Disease characteristics 1-5% of colorectal cancer cases AD, high-penetrance cancer syndrome (70-80%) cancers in colon, endometrium, small bowel, renal pelvis, ovary, and ureter Related genes MSH2 (40-60%), MLH (25-30%), PMS1, PMS2, MLH3, MSH6 all proteins involved in DNA mismatch repair → chromosome instability

31. Inherited Breast Cancer by mutations of BRCA1 and BRCA2 1-3% of all breast cancer cases 50-80% lifetime risk production of truncated proteins not seen in sporadic breast tumors Functions of BRCA1 and BRCA2 proteins interactions with RAD51 → repairing of DNA breaks interactions with tumor suppressor proteins (p53, pRb, Myc) * Mutations of PTEN (a tumor suppressor gene): Cowden disease, multiple benign tumors and breast cancer

32. Roles of BRCA1 and BRCA2 in DNA repair

33. Connections between BRCA1–BARD1 and the Fanconi anaemia proteins a, DNA damage activates ATM, ATR or other protein kinases, which (b) in turn, might activate the Fanconi anaemia (FA)-protein nuclear complex (dashed arrow) and are known to phosphorylate BRCA1 and FANCD2 (solid arrows) — this is required for the intra-S-phase checkpoint arrest by an uncertain mechanism. c, Activation of the FA- protein nuclear complex triggers mono- ubiquitylation of FANCD2, most probably through the FANCL protein. d, This results in the translocation of FANCD2 to nuclear foci that contain BRCA2, RAD51 and the MRE11–RAD50–NBS1 (M–R–N) complex. e, BRCA1–BARD1 is required for efficient FANCD2 accumulation in the foci, but the mechanism underlying this is not known. f, The BRCA1–BARD1 complex is also found in the foci. It is not yet understood precisely what reactions occur within the nuclear foci, which might contain hundreds of molecules of the accumulated proteins.

34. Familial Melanoma 5-10% of cases, inherited by mutation of CDKN2A gene (9p21, p16) loss of p16 function → activation of CDK4 → inhibition of pRb → a lack of cell cycle control →→ melanoma by mutation of CDK4 gain of function (oncogenic) activation of CDK4 →→ melanoma *sporadic melanoma by mutations of CDKN2A, BRAF (a kinase in RAS signalling), or APAF1 (in p53 apoptosis pathway)

35. Cell Cycle Regulation of Rb and E2F p16

36. RET proto-oncogene Functions of RET a receptor tyrosine kinase activated by GDNF and GFRα (a coreceptor) → embryonic neural crest cell migration Mutations of RET (10q) loss of function → abnormal embryonic development (eg. Hirschsprung disease) gain of function → various types of cancer multiple endocrine neoplasia 2A (MEN2A) multiple endocrine neoplasia 2B (MEN2B) familial medullary thyroid carcinoma Somatic mutations of RET → papillary thyroid carcinomas Cancer ↔ tuned genetic regulation ↔ Development