Cancer genetics

Question 1

What are the three kinds of cancers?

Answer 1

1. sarcomas: mesenchymal tissue (bone, muscle, neuronal)
2. carcinomas: epithelial tissue
3. hematopoietic and lymphoid: leukemia and lymphoma

Question 2

What are the genetic bases for cancer?

Answer 2

1. sporadic from somatic mutation

2. hereditary cancer syndrome - initial mutation is inherited through germline

Question 3

Mutations in what two types of genes lead to cancer?

Answer 3

Oncogenes (promote cell growth) and tumor suppressor genes (control cell growth)

Question 4

What are cancer stem cells?

Answer 4

original clone of neoplastic cells, provides reservoir of genetically unstable cells

Question 5

What is an example of an inherited oncogene?

Answer 5

RET - receptor tyrosine kinase, gain of function mutation, leads to medullary carcinoma of thyroid, pheochromocytoma, benign parathyroid adenomas

Question 6

How are oncogenes usually activated?

Answer 6

1. Point mutations - for example, Ras - turns GTP on and GDP off, keeps GTP on
2. Translocations - over 40 known, CML (9;22), Burkitt lymphoma t(8;14), Follicular B cell lymphoma t(18;14)

Question 7

What percentage of cancer cancers are hereditable?

Answer 7

5%

Question 8

What are the two types of tumor suppressor genes?

Answer 8

gatekeepers - directly regulate cell growth

guardians - repair DNA damage, maintain genome

Question 9

How is Retinoblastoma inherited?

Answer 9

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

Question 10

What does autosomal dominant and cellular recessive mean?

Answer 10

individual inherits one mutant copy of Rb but somatic mutation required in cell to knock out second copy of Rb –> “loss of heterozygosity”

Question 11

What risks go along with Retinoblastoma?

Answer 11

Rb has 95% cure rate however has 400x increased risk for other cancers like osteosarcoma, melanoma, breast cancer.

Question 12

What is characteristic of familial cancer?

Answer 12

2 or more primary cancers in same individual arising from different tissues

Question 13

What happens to the cell cycle with Rb hyperphosphorylated and hypophosphorylated?

Answer 13

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.

Question 14

What happens to E2F when Rb mutated?

Answer 14

Rb cannot bind to E2F so E2F is constituitively active.

Question 15

What is Li-fraumeni syndrome?

Answer 15

cancer families with cancer often appearing in young. Autosomal dominant but cellular recessive. Mutation is in p53. high probability wild-type copy will mutate.

Question 16

What is the mutation in FAP?

Answer 16

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.

Question 17

What is HNPCC?

Answer 17

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

Question 18

What is the genetic mutation in HNPCC?

Answer 18

cellular loss of both copies of mismatch repair gene, produces multiple alleles of microsatellite polymorphism in a single individual’s tumor DNA

Question 19

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?

Answer 19

avg woman - 9%
1 first degree relative - 3x
more than 1 first degree relative - 10x

Question 20

What are the 2 main loci involved in breast cancer?

Answer 20

BRCA1 and BRCA2, autosomal dominant and cellular recessive

Question 21

What is the function of BRCA 1 and 2?

Answer 21

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.

Question 22

What other cancers do BRCA1 and BRCA2 increase the incidence of?

Answer 22

BRCA1 - stomach, leukemia, and prostate cancer

BRCA2 - prostate and pancreatic cancer

Question 23

What is mutation is xeroderma pigmentosum?

Answer 23

autosomal recessive, mutation in excision repair pathway. Leads to hypersensitivity to UV light.

Question 24

What are the most common somatic mutations in sporadic cancers?

Answer 24

1. p53 - mutations in both copies in many sporadic cancers
2. RB1 mutated in many cancers including breast
3. BRCA1 or 2 mutated in half of sporadic breast cancers. mutations in both unseen but epigenetic modifications (methylation) more common.

Question 25

What is the screening criteria for BRCA 1/2

Answer 25

premenopausal onset of breast cancer, bilateral breast disease, at least one first degree relative with breast or ovarian cancer, 1 with both, multiple second degree relatives with breast or ovarian cancer, Ashkenazi Jewish descent with family hx, male breast cancer

Question 26

What are the 4 cardinal principles of ethics?

Answer 26

1. autonomy: individual’s right to control his/her medical care and information, free of coercion
2. Beneficence: do good for the patient
3. avoidance of maleficence: do no harm
4. Justice - treat all individuals fairly and equally

Question 27

What is reproductive cloning?

Answer 27

creation of genetically identical offspring

Question 28

What are problems in cloning?

Answer 28

imprinting is defective, few embryos survive, high rate of miscarriage, prolonged gestation with oversize birth

Question 29

Why are clones less identical than identical twins?

Answer 29

in utero environment diffferent, mtDNA different, physical environment different

Question 30

What are uses for gene therapy?

Answer 30

provide wild-type gene to correct disorder, inactivate dominant mutant gene, cells engineered for pharmacological effect.