Cancer Genetics

Question 1

Hits for mutation types

Answer 1

Tumor supp genes require loss of fx so need 2 hits. Protooncogenes are gain of fx so only need 1.

Question 2

Types of Oncogenic activation

Answer 2

Del/Pt mut leads to hyperactive protein in normal amts
Reg mutations leads to normal protein in mass amts
Gene amp leads to normal protein in mass amts
Chrome rearrangements can lead to either a mutation at reg site leading to overproduction or fusion which can lead to hyperactive protein due to loss of inhib domains

Question 3

Oncogene activation in hereditary cancer syndromes

Answer 3

1 hit cancers = Multiple Endocrine Neoplasma type 2 (MEN2) and Hereditary Papillary Renal Carcinoma

Question 4

MEN2

Answer 4

AD, familial cancer syndrome, affects 2 or more endocrine glands (medullary thyroid carcinoma, pheochromocytoma [adrenal glands: high BP])
Gain of fx in RET (RTK; cons activated)

Question 5

Hereditary Papillary Renal Carcinoma

Answer 5

MET (HGFR) mutation - involved in embryonic development and wound healing (normal in stem cells). Cons activation of MET leads to tumor growth, angiogenes, and metastasis.

Question 6

Oncogene activation in sporadic cancer

Answer 6

RAS activation (fx in many cancers) - RAS involved in activation of MAPK after growth factor activation

Question 7

Oncogene activation by chronic translocation Syndromes

Answer 7

Burkitt Lymphoma (8;14), Malignant Follicular Lymphoma (14;18), Chronic Myeloid Leukemia (9;22), Acute Promyelocytic Leukemia (15;17), Ewing Sarcoma (11;22)

Question 8

Burkitt Lymphoma

Answer 8

t(8;14), translocates protooncogene MYC distal to Ig heavy locus on 14, so MYC under ctrl of strong Ig promoter leading to overexpression. Non hodgekins lymphoma. Endemic in Africa (EBV); non endemic = ileocecal or peritoneal mass

Question 9

Malignant Follicular Lymphoma

Answer 9

t(14;18), Bcl-2 placed under strong Ig promoter. Bcl-2 is anti-apoptotic and overexpression leads to cell proliferation

Question 10

Chronic Myeloid Leukemia

Answer 10

t(9;22), Fusion of two genes (Philly chromosome), 9=ABL an intracell signal kinase involved in promoting cell proliferation. Splicing together leads to new protein with cons activated kinase activity = cell proliferation. Chronic phase has 3yr survival with BM/stem cell transplant. Blast crisis is treated to bring back to chronic (increased cytogenic rearrangements)

Question 11

CML treatment

Answer 11

Imantinib/Gleevac = BCL-ABL tyrosine kinase competitive inhibitor

Question 12

Acute Promyelocytic Leukemia

Answer 12

t(15;17), Fusion of PML-RARalpha leading to overactive kinase. RAR-alpha is retinoic acid receptor which is a nuclear receptor and TF. Promotes prolonged proliferation and turns off genes required for myeloid differentiation.

Question 13

Ewing Sarcoma

Answer 13

t(11;22), EWS-FL1 fusion (FL1=TF). Small round cell tumors of soft tissues and long tubular bones. 30% metastatic at presentation

Question 14

Oncogene activation by amplification

Answer 14

MYC amplification in many cancers. N-MYC in neuroblastomas = neuroendocrine tumor (SNS), tumors of adrenal medulla or along sympath ganglion. Extra chromosomal double minutes and in chromo 2p, hundreds to copies of MYC gene.

Question 15

Tumor suppression genes

Answer 15

Loss of fx, 2 hit model, AD cancer symptoms, chrome instability syndrome in sporadic cancers. Normally inherit 1 hit allele, need 2nd mutation to have founder cell of tumor, 2nd hit can be epigenetic (hypermethylation at CpG and silencing of normal gene)

Question 16

Genetics presentation

Answer 16

Familial always bilateral and early onset (similar to AD). Sporadic is unilateral and later onset (2 hits rqrd)

Question 17

Inherited Cancer syndromes

Answer 17

Retinoblastoma, Li-Fraumeni Syndrome, Neurofibromatosis, Familial Breast Cancer, FAP, HNPCC

Question 18

Retinoblastoma

Answer 18

Rb1 mutation - rare malignant tumor of the eye. white reflex. If Rb is missing, there is nothing to lock E2F therefore it is always able to promote cell cycle

Question 19

Rb1

Answer 19

Phosphoprotein, phosphorylated by cyclinD/Cdk4 and releases E2f which transcribes Cyclin E and promotes cell cycle. Hypophos inhibits G1 to S transition.

Question 20

Li-Fraumeni Syndrome

Answer 20

Inherited p53 mutation, AD, high incidence of many different cancers. Loss of p53 allows dmg’d cells to survive and proliferate

Question 21

p53 gen

Answer 21

gatekeeper = DNA binding protein transcriptor of DNA repair enzymes and cell cycle arrest genes. Induces apoptosis (if irreparable dmg)

Question 22

Neurofibromatosis

Answer 22

Mutation in NF1, 50% sporadic. Many benign tumors leading to hyperpigmentation regions, AD, complete penetrance by age 5. With plexiform neurofribroma, freckles, and cafe au lait/lisch nodules.

Question 23

NF1

Answer 23

Inactivates RAS protooncogene = RAS GAP; increases GTPase of RAS. Mutation leads to active RAS leading to inappropriate growth and tumor formation.

Question 24

Familial Breast Cancer

Answer 24

Mutation in BRCA1 (17q21) and BRCA2 (13q12). 3x risk if 1 primary, 10x risk if more than 1 primary relative. Early onset, multi and bilateral. BRCA 1 (FM breast and ovarian cancer) BRCA2 (FM breast and ovary, male breast, and prostate cancer)

Question 25

BRCA

Answer 25

repairs DNA dmg (both single and double)

Question 26

Familial Colorectal Cancer

Answer 26

AD
FAP - Mutation in APC (serine Thr kinase)
HNPCC = mutation in caretakers/DNA repair enzymes

Question 27

FAP

Answer 27

Mutation in APC, heterozygous develops mutliple adementous polyps (benign) in colon epithelium (more polyps = malignant)

Question 28

APC

Answer 28

Beta-catenin stimulates proliferation by binding transC factors in nucleus and activates MYC leading to Cyclin D. APC phosphorylates and free beta catenin to prevent proliferation and possible degradation

Question 29

WNT signal pathway

Answer 29

WNT binds to frizzled and activates disheveled. Disheveled inhibits APC complex therefore beta catenin is not phosphorylated so not degraded leading to beta accumulation promoting proliferation.

Question 30

Colon epithelium

Answer 30

Stem cells located in crypts and constantly divide to provide new epi cells. WNT signalling is normal at bottom and switched off as cells migrate to the top as cells exit cycle and differentiate. WNT inactivates APC therefore preventing phos of Beta-catenin leading to cell proliferation. As cells migrate up, WNT signal stops and APC activated phos Beta and enables differentiation.

Question 31

HNPCC

Answer 31

AD, colon cancer without polyps and mutations in DNA repair genes. Homozygous cells (loss of DNA repair genes has point mutations leading to instability of simple repeats and microsatellite polymorphisms = instability and replication errors (RER pos))

Question 32

HNPCC TGFB-R2 mut

Answer 32

Mutations occur secondary to repeat instability in TSGs and oncogenes. Microsatellite instability and accum of point mutations. Leads to loss of pro-apop signal pathway

Question 33

Sporadic cancers

Answer 33

Loss of TGFBR2/SMAD4, Loss of PTEN, Loss of WT-1

Question 34

Loss of TGFBR2 and SMAD4

Answer 34

SMAD4 promotes apoptosis and loss of SMAD4 promotes upreg growth. Both part of growth inhib signal cascade. TGFBR2 loss of fx in HNPCC and RER pos sporadic colon cancer

Question 35

Loss of PTEN

Answer 35

Normally induces apoptosis by down reg of bcl-2. Loss of PTEN leads to upreg of bcl-2 therefore blocking apoptosis and promotes cell cycle. Deleted in many cancers, high freq in prostate cancer, endometrium, glioblastoma.

Question 36

PTEN

Answer 36

promotes apoptosis by converting PIP3 to PIP2 therefore preventing export of bcl-2

Question 37

Loss of WT-1

Answer 37

Found in hereditary and sporadic Wilm’s tumor = pediatric kidney cancer. Involved in renal differentiation. If lost, cells keep proliferating

Question 38

Chromosome instability Syndromes

Answer 38

Not cancers but are conditions that increase chances of developing cancer. 2 alleles must be inherited, heterozygous more common and increases malig risk.

XP, Ataxia Talen, Bloom syndrome, Werner Syndrome, Fanconi Anemia

Question 39

Xeroderma Pigmentosa

Answer 39

Defect in nucleotide excision repair (NER). Absorption of UV light leads to formation of pyrimidine dimers and increased risk of skin cancers

Question 40

Ataxia Talengiectosia

Answer 40

Mutation in ATM - is a kinase that phos p53 leading to its accumulation (prevents mdm2 binding). Also a defect in DNA repair by homologous recombination.

Question 41

Bloom Syndrome

Answer 41

BLM = DNA helicase. Loss of fx = high frequency of chromosome breaks and rearrangements. Hypersensitivity to ionizing radiation. Chromo instability leads to high risk for many cancers (solid tumors). Immuno def.

Question 42

Werner Syndrome

Answer 42

Mutation in WRN = DNA helicase and exonuclease. Unwinds DNA and trims broken ends of dmg’d DNA. Patients have shorter telomers and impaired DNA rep leading to premature aging at puberty

Question 43

Fanconi Anemia

Answer 43

AR childhood, multi-chromosome breaks. BM fail: pancytopenia, risk of NML, skl abnorm (UL). DNA defects in repair.

Question 44

miRNA and cancer

Answer 44

blocks translation or degrades target mRNA. Glioblastoma multiform=100x miRNA

Question 45

Tumor viruses

Answer 45

able to transform cells and increase cancer risk

Question 46

EBV

Answer 46

Burkitts lymphoma (t[8;14]) B cell lymphoma in immunocomp pts

Question 47

HEP B and C

Answer 47

hepatic cancer with chronic infection

Question 48

HTLV-1 retrovirus

Answer 48

T cell leukemia

Question 49

HIV retrovirus

Answer 49

leads to opportunistic neoplasms. Kaposi Sarcoma (HHV-8) and EBV nonhodgekins lymphoma (usually in brain with focal neurologic signs and mental status changes)

Question 50

HPV

Answer 50

HPV oncogenes = E6 and E7
E6 binds and inhibits Tb = unctrld entry to S
E7 binds and inhibits p53