Angela's Genetics Flashcards
What is the most common cause of a germline mutation?
Loss of heterozygosity
What are common hereditary tumor suppressor proteins in endometrial cancer?
LYNCH
MLH1 (3p22)
MSH2 (2p21)
MSH6 (2p16)
PMS2 (7p22)
EPCAM (2p21)
COWDEN
PTEN (10q23)
(Updated from Chi table)
What are common sporadic tumor suppressor proteins in endometrial cancer?
PTEN (10q24), p53 (17p13)
What is the translocation in Burkitts?
Which protein is overexpressed?
[t(8;14)]
myc protein
What is the translocation in CML?
Which protein is overexpressed?
[t(9;22)]
Abl
The Philadelphia chromosome is a reciprocal translocation involving chromosomes 9 and 22 that is commonly identified in chronic myelogenous leukemia (CML). The break points of the translocation create a fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22.
Where is Rb gene located?
13q14
What is the chromosomal abnormality associated with etoposide-induced AML?
Rearrangements at 11q23
it’s a stretch, but: 32pos1de-1nduced AML
What are tumor suppressor genes?
Genes that normally inhibit cell proliferation, loss of heterozygosity
What are common hereditary tumor suppressor proteins affected in ovarian cancer?
BRCA1 / 2, MSH2
What are common sporadic tumor suppressor proteins affected in ovarian cancer?
p53 (encoded by TP53 on 17p13), p16 (encoded by CDKN2A)
What is the most common epigenetic step responsible for deactivating the second tumor-suppressor gene in the process of carcinogenesis?
Hypermethylation of CpG islands in the promoter region
Hypermethylation silences the promoter thus inhibiting transcription of the protein
What epigenetic step is critical to deactivating many tumor-suppressor genes?
Methylation of CpG islands in promoter regions
Which of the following are not associated with hereditary cancer susceptibility?
A) RB
B) P53
C) MSH
D) BRCA 1
E) Her 2 neu
E) Her 2 neu
What does the HPV protein E6 bind to?
P53
What is the most commonly inactivated gene described for human cancers?
P53
What is the gene locus of p53?
17p13
What is the most common mutation found in p53?
Single nucleotide missense mutation in the middle third (exons 5-8) of the gene leading to inactivation of any remaining normal P53 in the nucleus.
Mutation of one copy of the gene is accompanied by deletion of the other copy of the gene leading the cancer cell with only mutant P53 protein.
What is the function of p53?
“Guardian of the genome”
It activates genes involved in DNA damage repair pathways at G1-S and G2-M checkpoints to prevent replication and mitosis in damaged cells by inducing apoptosis
Where is p53 located in the cell?
Intranuclear
How does p53 stall the cell cycle?
Cellular damage –> induces p53 –> induces CIP/WAF/p21
–>prevents CDK phosphorylation –> prevents Rb phosphorylation
–> stops cell cycle –> eventually leading to apoptosis
What occurs with a mutation in P53?
Mutated p53 protein accumulates in nucleus and cannot bind to DNA, interfering with wild type p53 function
What is the most common mutation in UPSC?
p53
What is the gene defect in LiFraumeni?
p53
LiFraumeni is associated with increased risk of what cancers?
Sarcoma, breast, brain, leukemia, melanoma, GI
*important for us to know sarcoma, breast
LiFraumeni is also known as SBLA Syndrome (Sarcoma, Brain, Breast, Leukemia, Adrenal cortical)
Mnemonic: Could think of BLABS: breast, leukemia, adrenal cortical, brain, sarcoma
Which diagnostic criteria must be fulfilled for Li Fraumeni?
- Sarcoma < 45yo
- First-degree relative with any cancer <45
- Another 1 or 2 degree relative with any young cancer or any sarcoma
What is the location of PTEN?
10q23
Is PTEN a Tumor suppressor or Oncogene?
Tumor suppressor
What does PTEN encode?
A tyrosine phosphatase that inhibits FAK, ERK, MAPK
ERKs (extracellular-signal-regulated kinases)
focal adhesion kinase (FAK)
mitogen-activated protein kinase (MAPK)
When PTEN is mutated and nonfunctional, which pathway is allowed to proceed?
PI3K/AKT pathway
What is the most common mutation in endometrial cancer?
PTEN
Which ovarian cancer histology exhibits higher levels of PTEN mutation?
Endometrioid OVCA
What mutations is associated with Cowden’s Syndrome?
PTEN
What cancers are associated with Cowden’s Syndrome?
Breast, endometrial, thyroid, and hamartomas
Mnemonic: “Pettin’ my cow Beth”
PTN - COWden - Breast/Endometrial/Thyroid/Hamartoma
How is Cowden’s inherited?
Autosomal dominant
What is Bannayan/Zonana?
Similar to Cowden’s
Caused by PTEN mutation
Bannayan-Zonana syndrome is a rare hamartomatous disorder, characterized by macrocephaly, multiple lipomas, and hemangiomas. Inheritance is by autosomal dominant transmission with few reported sporadic cases. Male predominance is also reported.
What are the roles of BAD BAX and BID?
All pro-apoptosis.
Proteins of the Bcl-2 family
What does downregulation of BAD, BAX or BID cause?
Decreased apoptosis, increased tumorogenesis
What are the genetic mutations associated with Lynch?
MSH2, MLH1, MSH6, PMS2
What chromosome is MLH1 located on?
3p22.2
What chromosome is MSH2 located on?
2p21-16
What does the MSH2 protein interact with?
MSH6
What is the heritability of Lynch syndrome?
Autosomal dominant
Are MLH1, MSH2 tumor suppressor genes or a proto-oncogene?
Tumor suppressor genes
What is the mechanism of instability initiated by a mutation in MLH1 and MSH2?
Mismatch repair causes microsatellite instability
What screening is recommended for patients with Lynch?
Annual colonoscopy at age 20-25, annual EMB at age 35
Where are colon cancers associated with Lynch likely to originate?
Proximal to the splenic flexure
*Lynch Syndrome is also known as hereditary non-polyposis colorectal cancer (HNPCC)
At what age is Hysterectomy recommended for patients with HNPCC (Lynch)?
NCCN: At completion of childbearing. May consider annual endometrial biopsy starting between age 30 and age 35
ASCO and ESMO say 35
SGO and ACOG say 40-45
Where in the colon do Lynch cancers occur?
Proximal colon