Cancer genetics Flashcards
(30 cards)
What are the three kinds of cancers?
- sarcomas: mesenchymal tissue (bone, muscle, neuronal)
- carcinomas: epithelial tissue
- hematopoietic and lymphoid: leukemia and lymphoma
What are the genetic bases for cancer?
- sporadic from somatic mutation
2. hereditary cancer syndrome - initial mutation is inherited through germline
Mutations in what two types of genes lead to cancer?
Oncogenes (promote cell growth) and tumor suppressor genes (control cell growth)
What are cancer stem cells?
original clone of neoplastic cells, provides reservoir of genetically unstable cells
What is an example of an inherited oncogene?
RET - receptor tyrosine kinase, gain of function mutation, leads to medullary carcinoma of thyroid, pheochromocytoma, benign parathyroid adenomas
How are oncogenes usually activated?
- Point mutations - for example, Ras - turns GTP on and GDP off, keeps GTP on
- Translocations - over 40 known, CML (9;22), Burkitt lymphoma t(8;14), Follicular B cell lymphoma t(18;14)
What percentage of cancer cancers are hereditable?
5%
What are the two types of tumor suppressor genes?
gatekeepers - directly regulate cell growth
guardians - repair DNA damage, maintain genome
How is Retinoblastoma inherited?
40% of cases are inherited and 75% of those are a new mutation, familial has earlier age of onset and produces bilateral tumor. Autosomal dominant but cellular recessive. 90% penetrant
What does autosomal dominant and cellular recessive mean?
individual inherits one mutant copy of Rb but somatic mutation required in cell to knock out second copy of Rb –> “loss of heterozygosity”
What risks go along with Retinoblastoma?
Rb has 95% cure rate however has 400x increased risk for other cancers like osteosarcoma, melanoma, breast cancer.
What is characteristic of familial cancer?
2 or more primary cancers in same individual arising from different tissues
What happens to the cell cycle with Rb hyperphosphorylated and hypophosphorylated?
Hypophosphorylation keeps Rb bound to E2F and prevents entry into cell cycle, Hyperphosphorylation kicks off Rb from E2F and promotes entry into cell cycle. E2F turns of S-phase genes, CDK phosphorylates Rb.
What happens to E2F when Rb mutated?
Rb cannot bind to E2F so E2F is constituitively active.
What is Li-fraumeni syndrome?
cancer families with cancer often appearing in young. Autosomal dominant but cellular recessive. Mutation is in p53. high probability wild-type copy will mutate.
What is the mutation in FAP?
APC gene, which is normally responsible for degrading beta catenin. Undegraded Beta catenin can activate cell proliferation genes including myc. No WNT signalling required to turn off APC.
What is HNPCC?
Hereditary Nonpolyposis colon cancer (HNPCC), autosomal dominant. Males have 90% risk of colon cancer, females have 70% risk of colon cancer but 40% risk of endometrial cancer and 10-20% biliary, urinary, or ovarian cancer
What is the genetic mutation in HNPCC?
cellular loss of both copies of mismatch repair gene, produces multiple alleles of microsatellite polymorphism in a single individual’s tumor DNA
What are the risks for breast cancer is average woman, woman with first degree relative with breast cancer, woman with more than 1 first degree relative with breast cancer?
avg woman - 9%
1 first degree relative - 3x
more than 1 first degree relative - 10x
What are the 2 main loci involved in breast cancer?
BRCA1 and BRCA2, autosomal dominant and cellular recessive
What is the function of BRCA 1 and 2?
both genes involved in double strand break repair and homologous recombination, BRCA1 also involved in transcription coupled repair from UV light or oxidative DNA damage.
What other cancers do BRCA1 and BRCA2 increase the incidence of?
BRCA1 - stomach, leukemia, and prostate cancer
BRCA2 - prostate and pancreatic cancer
What is mutation is xeroderma pigmentosum?
autosomal recessive, mutation in excision repair pathway. Leads to hypersensitivity to UV light.
What are the most common somatic mutations in sporadic cancers?
- p53 - mutations in both copies in many sporadic cancers
- RB1 mutated in many cancers including breast
- BRCA1 or 2 mutated in half of sporadic breast cancers. mutations in both unseen but epigenetic modifications (methylation) more common.
