Lynch Syndrome: An Updated Review

Abstract

Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers

“…4 LS is caused by germline mutations in one of four mismatch repair (MMR) genes or by a deletion in the EPCAM locus affecting the adjacent MMR gene. 5 These germline mutations result in defective MMR machinery that leads to microsatellite instability (MSI) throughout the genome and gives rise to tumors. Both Lynch-related and sporadic cancers can manifest MSI.…”

Papillary thyroid carcinoma (PTC) in Lynch syndrome: Report of two cases and discussion on Lynch syndrome behaviour and genetics

“…The majority of colorectal cancers (CRC) develop sporadically from somatic alterations in colon epithelial cells; however in up to 30% of cases, CRC develops in patients that have a strong family history [2].…”

“…A woman who worked as his seamstress reported distress over the fact that many family members over several generations had succumbed to cancer and she feared the same for herself. Indeed she developed endometrial cancer, and died of that disease as she predicted [2,4]. Warthin studied her family in detail and published this large pedigree at 10 affected family members in 1913 outlining many generations affected by colonic, gastric, and uterine cancers [5,6].…”

“…HNPCC [2,4]. A woman who worked as his seamstress reported distress over the fact that many family members over several generations had succumbed to cancer and she feared the same for herself.…”

Identification and verification of a pathogenic MLH1 mutation c.1145dupA in a Lynch syndrome family

“…Lynch syndrome (LS), an inherited cancer predisposition syndrome with a substantially increased risk of colorectal and endometrial cancer, along with increased risk of malignant ovarian, gastric, small bowel, brain, hepatobiliary, pancreatic, kidney, bladder, urothelial, prostate, and breast tumors, is caused by germ-line mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 [1][2][3][4][5][6][7][8][9][10][11] . The majority of Lynch syndrome cases (69%-90%) arise from germ-line MLH1 and MSH2 mutations; carriers of MSH6 and PMS2 mutations account for the rest [12][13][14][15] .…”