There are genetic and environmental factors that influence cancer development. While some cancers have a strong hereditary component, the majority of cancers are caused by environmental exposures and acquired somatic mutations. Key genetic factors include oncogenes that promote cell growth and tumor suppressor genes whose mutations allow for unchecked cell division. Epigenetic changes like DNA methylation and histone modifications can also influence cancer risk by altering gene expression without changing the underlying DNA sequence.

1. Cancer genetics

2. Cancer genetics “ all cancer is genetic, but some cancers are more genetic than others” “ cancer runs in families”

3. Cancer genetics acquired somatic genetic diseases 95% of all cases somatic mutation mostly caused by environmental factors hereditary cancer 5% of all cases susceptibility/major genes germline mutation

4. Differentiation between genetic and environmental factors in cancer 1. epidemiological study: breast cancer association with reproduction and menstruation having children vs. nulliparous first menstrual age: early vs. late indicative in genetic vs. environment incidence highest in European origin populations 8 times lower in Chinese, Japanese indicating genetic component migration migration from low to high incidence areas: increased incidence indicating environmental factors

5. Differentiation between genetic and environmental factors in cancer 2. family study breast cancer incidence risk 1.5-3 folds than general population , if having one 1st degree relative patient gastric cancer risk 2-3 folds than general population if one 1st degree relative patient liability curve 3. twin study concordance rates for breast cancer monozygotic twins: 17% dizygotic twins: 13% indicating importance of environment

7. Differentiation between genetic and environmental factors in cancer 4 . association study blood group A people have an 20% increased risk for gastric cancer over the general population 5. animal models 6. viral factors DNA viruses: table 14.1, p198 retroviruses: RNA – DNA (reverse transcriptase) – integration into host genome

9. Oncogenes concept proto - oncogen normal cellular genes have key roles in cell growth and differentiation have the potential to be tumorogenic oncogene converted from proto – oncogene has tumorogenic (carcinogenic) effects cellular oncogene (C-oncogene) cellular origin has tumorogenic (carcinogenic) function viral oncogene (V-oncogene) viral origin has tumorogenic (carcinogenic) property

10. Oncogenes identification of oncogenes 1. at chromosomal translocation breakpoints Philadelphia chromosome: Fig in Li Pu’s book Burketts lymphoma chromosome: Fig in Li Pu’s book 2. amplification of oncogenes 10,000, or 1,000 folds of increased gene copies ERBB2 gene copy number increased 20% in breast cancer cases MYC gene copy number increased 30% neuroblastoma cases

11. Philadelphia chromosome

12. Burketts lymphoma gene

13. Oncogenes Types of oncogens growth factor: v-SIS gene: codes for part of platelet-derived growth factor HST : homologous of fibroblast growth factor growth factor receptors: ERB-B : epidermal growth factor receptor intracellular signal transduction factors: proteins with GTPase activities RAS genes cytoplasmic serine threonine kinases RAF gene DNA-binding nuclear proteins: transcription factors FOS, JUN cell cycle genes: loss of cell cycle inhibitory genes cyclin-dependent kinases cyclin D1 loss of genes lead to apoptosis

14. Tumor suppressor genes RB1 and retinoblastoma retinoblastoma phenotype: Fig hereditary non-hereditary two-hint theory: Fig loss of heterozygosity (LOH) Fig 14.7, p204 table 14.2, p205

19. TP53 and Li-Fraumeini syndrome TP53 : the most mutated tumor suppressor genes in cancer checkpoint control of G1-> S Li-Fraumeini syndrome: phenotype: familial cancer multiple organ cancers TP53 somatic and germ-line mutations familial cancer due to tumor suppressor gene mutation table 14.3, p208

20. Tumor suppressor genes

21. Epigenetics and cancer epigenetics 1. concept heritable changes to gene expression that are not due to difference in gene code (DNA sequence), transmitted either through mitosis or meiosis 2. roles imprinting the phenomenon of a gene or a region of a chromosome showing differential expression depending on the parent of origin. Fig 7.22 X-inactivation regulation of gene expression

22. Prader-Willi and Angelman syndrome genes

23. Epigenetics and cancer 3. mechanisms of epigenetics re-imprinting in gamatogenesis methylation of DNA sequences reduced expression maintain genome stability chromatin remodeling (histone modification) condensed or loosened super-coil structures changes in transcriptional activity of sex genes during development 4. epigenetics in cancers hypomethylation of oncogenes hypermethylation of tumor suppressor genes

24. Telomere length and cancer telomere: chromosomal ends tandem repeats: TTAGGG for 10-15 Kb length maintained by telomerase shortened telomere in cancer aging Fig 14.9

25. Telomere length and cancer

26. Genetics of common cancers colorectal cancer 1. multistage hypothesis of carcinogenesis Fig 14.10

27. multistage hypothesis of carcinogenesis

28. Multistage (multistep) theory

29. Genetics of common cancers colorectal cancer 2. familial adenomatous polypsis (FAP) phenotype: Figs x 2 genetics: autosomal dominant APC gene treatment: prophylactic colectomy

30. hereditary familial adenomatous polyposis

32. Colorectal cancer 3. hereditary non-polypsis colorectal cancer (HNPCC) phenotype: less polyps site specific: proximal right genetics: autosomal dominant gene: DNA mismatch repair genes table 14.4 microsatellite instability (MSI) (replication error) somatic or germline

34. Breast cancer 1. incidence in west: 1 in 12 women aged 40-55 1 in 3 will be metastatic 2. genetics (somatic form): cumulative changes amplification: ERB-B1 ERB-B2 LOH: 7q, 16q, 13q, 17p, etc Fig 14.7

36. Breast cancer 3. familial breast cancer (1) autosomal dominant (2) BRCA1 : chr 17 mutations in 40-50% early onset families lifetime risk for family members: 60-85% if having the mutation increased risk for : ovarian cancer in female prostate cancer in male

37. Breast cancer (3) BRCA2 , chr 13 30-40% early onset autosomal dominant families female mutations carriers lifetime risk for family member as BRCA1 heterozygotes: increased risk of ovarian cancer male mutations carriers 6% lifetime risk for breast cancer, which is 100 - fold increased risk in comparison with the general population

38. Genetic counseling in familial cancer inherited cancer-predisposing syndrome individual has more than one site cancers or at different sites in various individuals of a family than would be expected box 4.1 risk estimation table 14.6, 14.7

40. Risk estimation

42. Genetic counseling in familial cancer screening for familial cancer phenotype screening genotype screening treatment prophylactic medications: Asprin in FAP tamoxifen for breast cancer (anti - estrogen) life style change prophylactic surgery: table 14.9