Lynch Syndrome Flashcards
What are the symptoms of Lynch (HNPCC) Syndrome?
increased risk of colorectal cancer (70 percent). Early onset, the average is 44. Gastrointestinal bleeding, abdominal pain) INcreased incidence of synchronous and metachoronous CRC (within 6 months of the first detection or more than 6 months.) disorganized villi, and more likely to develop on right side of colon (at the splenic flexure)
Out of 100 cases of CRC in the united States…
3 will have Lynch syndrome
.01 person will have familial adenomatous polyposis.
What is the difference between familial cancer and hereditary cancer?
A cluster of cancers that likely occurs by chance. There is a combination of genetic and nongenetic factors that contribute to the development of cancers within a family. They may just face an elevated risk of cancer.
Hereditary means the defect of a single major gene strongly contributes to the development of cancer.
What other cancers does Lynch cause a predisposition to?
endometrial, stomach, ovaries, bowel, brain.
Discuss the repair enzymes.
mutations in mSh2 or MLH1 results in high MSI, except MSH6. Single base base mismatches are bound by the MSH2-MSH6 complex and the insertion deletion loops are recognized by MSH2 and 3.
MSH2/6 recruits endonucleases MLH1 and PMS2.
Difference between forward and backward slippage.
Forward is where a loop in the template MS region is formed and the replication misses that loop leading to Deletion.
Backward is when the MS (full of repeats) the polymerase accidentally repeats the reading and this results in an insertion.
How to read MSI instability.
PCR, you use the flanking sequences as primer and analyze PCR products. If a wide spread of bands, shows MSI. You look at at least 5 microsatellite loci. 2 or more markers indicate high instability. 1 marker is low. and 0 is normal.
Another way is immunohistochemistry (cheaper) for any of the repair enzymes. However MLH1/PMS2 and MSH2/6 are always linked so dissapearance of one will have the same effect on the other.
Colonoscopy…
Is the only screening that can detect cancer.
Describe Amsterdam and Bethesda Criteria
Amsterdam (3-2-1) 3 first degree relatives with HNPCC associated cancer
Cases span at least 2 generations
At least one cancer case diagnosed before 50 years.
Bethesda - is more lax
Lead to population screening - everyone with colorectal cancer and family members of those affected with lynch syndrome.
Lynch syndrome subtypes:
Constitutional Mismatch repair deficiency: biallelic inheritence, coffee colored spots
PPAP (mutations in POLE and POLD1 genes, lynch like syndrome. Microsatellite stable.)
Turcot: lynch with CNS disorders
MUir Torre: lynch with skin lesions.
Aside maybe Increased risk of prostate cancer, highest risk was with MSH2 mutations.
