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Terms in this set (57)
Colorectal Cancer (CRC) is the __ most common cancer in men and women
(excluding skin cancers)
What is the lifetime risk to develop CRC?
1 in 19
What is the function of the Colon and Rectum?
to absorb fluid to form solid waste (fecal matter) that then passes from the body
What are the sections of the colon?
Ascending (up on rt side)
Descending (down on left)
What is the rectum?
Final 6 inches of digestive system, stores waste until passes through anus
what are the types of Polyps?
Hyperplastic (low risk)
What is the most common type of colon polyp?
Which type is most likely to progress to cancer?
Adenomas (to adenocarcinoma - 95% of all CRC)
What cancer syndromes are adenomas associated with?
HNPCC, FAP, MAP
What Cancer syndromes are hamartomatous polyps associated with?
JPS, PJS, PTEN, Gorlin, MEN2B, NF1
What are general risk factors for CRC?
age, hx of polyps or IBS, FHx, Race (AA, AJ), red meat, physical inactivity, smoking, obesity, alcohol, type 2 diabetes
what % of new CRC cases are due to HNPCC?
What are the genes implicated in HNPCC?
MLH1 (3p, 90%)
MSH2 (2p, 90%)
MSH6 (2p, 7-10%)
PMS2 (7p), 4%)
What are the cancer risks associated with HNPCC?
COBDEBSHUS: colorectal, ovary, brain, duodenum, endomet, B____, stomach, hepatobilliary, urinary tract, sebaceous skin
HNPCC: lifetime risk for CRC?
82% (5.5% gen pop)
HNPCC: lifetime risk for endometrial cancer?
71% (1.5% gen pop)
HNPCC: lifetime risk for stomach cancer?
13% (less than 1%)
HNPCC: ovary cancer risk?
HNPCC: risks for urinary tract, brain, biliary tract, small bowel?
up to: 5%, 3%, 7%, 4%
HNPCC: What is the risk for a second cancer after 10 years? after 15 years?
30% in 10 yrs
50% in 15 yrs
what types of genes are implicated in HNPCC?
Mismatch repair (MMR)
What do MMR genes do?
recognize and repair erroneous insertions, deletion, misincorporation of bases that arise, 4 of 5 assoc with HNPCC
What is the common pathological finding of HNPCC cancers?
Microsatellite instability (MSI)
(particularly susceptible to acquiring errors when MMR gene function is impaired)
How is MSI assessed?
based on panel, greater than 30% is MSI-High, less is MSI-LOW, 0% is MSI-Stable
What % of MSI-High tumors are associated with HNPCC mutations?
What % of HNPCC tumors are MSI-High?
What can you learn from immunohistochemical (IHC) evaluation of a tumor?
Which genes you should target for testing
What does Loss of hMSH2 (and hMSH6) mean?
What does Loss of hMLH1 (and PMS2) mean?
What does Loss of hMSH6 ALONE mean?
What does Loss of PMS2 ALONE mean?
What is a BRAF V600E mutation/CpG methylation?
can cause silencing of MLH1 gene, causes MSI-H and loss of MLH1 protein expression but NOT MLH1 germline mutation
If IHC shows loss of hMLH1, what should you do?
make sure BRAF mutation is negative before continuing with MLH1 sequencing
What geno-pheno correlation is MSH2 mutations associated with?
greater frequency of extracolonic ancer, lower freq of CRC compared to MLH1
What are MSH6 mutations associated with?
inc freq of endomet cancer, inc risk of rectal cancer, later cancer onset
What are PMS2 mutations associated with?
lower risks compared to MLH1 and MSH2; 1/4 Males, 1/3 females dx with cancer by age 70
What is the avg age of CRC in HNPCC vs gen pop?
45 vs 69
What side is HNPCC CRC usually on?
70% right side (proximal to splenic fixture)
How does carcinogenesis (polyp to cancer) compare in HNPCC vs gen pop?
2-3 yrs vs 8-10 yrs
What is the risk of additional CRC in HNPCC?
25-30% within 10 yrs if don't have total colectomy
What is the Muir-Torre variant of HNPCC?
1+ internal malig, sebaceous neoplasms of skin (adenomas, epitheliomas, carcinomas, keretoacanthomas), exhibit MSI
What is the Turcot variant of HNPCC?
CRC/adenomas, CNS tumors, can be caused by APC or MMR mut, glioblastomas (MMR), meduloblastomas (APC)
What are homozygous MMR mutations associated with?
CRC in childhood, hematological cancer, brain tumors, cafe-au-lait macules, NF-type manifestations
What is Familial Colorectal Cancer Type X?
fams that fit AC-I but dont have MMR mut (40%), if MSI-H have higher ca risk, do not counsel like HNPCC
What is Amsterdam Criteria used for?
determining if family should undergo comprehensive genetic testing
What is Bethesda Guidelines used for?
determining if family qualifies for MSI testing (if tumor block available)
What is Amsterdam Criteria I?
3+ fam members (FDRs) with CRC
2 successive generations
1+ CRC dx before 50
What is Amsterdam Criteria II?
Same but includes colon, duodenal, endometrial, ureter or renal pelvis)
What is the sensitivity of AC1/AC2 for MSH2/MLH1 mutations?
(specificity goes down with wider criteria)
What are Bethesda Guidelines?
CRC dx before 50 plus other LS tumor, MSI-H ca before 60, LS tumor in FDR before 50, LS tumor in two F/SDR at any age
What is the detection rate if clinical presentation and FHx is convincing?
What is the det rt if AC1 met, MSH-H, IHC shows loss of MMR?
1 in ___ ppl with CRC have HNPCC?
1 in 35
HNPCC mutations account for what % of Familial CRC?
What does comprehensive COLARIS testing include and how much does it cost?
full seq and rearrang analysis of MLH1,MSH2, seq of MSH6 ($2950)
How much does COLARIS single site testing cost?
How much does MLH1/MSH2/MSH6 testing cost?
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