Abstract
The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available. We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample. The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7). Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.
Highlights
Lynch Syndrome (LS), formerly known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most common hereditary colorectal cancer syndrome and accounts for 3– 5% of CRC cases.[1]
Cumulative risk of endometrial cancer (EC) was 55.64% with overall hazard ratio (HR) of 66.7 (41.7–106.7)
Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation
Summary
Lynch Syndrome (LS), formerly known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most common hereditary colorectal cancer syndrome and accounts for 3– 5% of CRC cases.[1]. While there have been a variety of tumor types described in LS, adenocarcinomas of the colorectum and endometrium are the most common, and clinical management guidelines recommend aggressive surveillance and risk reducing surgery for these cancers.[2] Previously, a rare founder mutation MSH2*1906C>G, known as A636P was described in Ashkenazi Jews[3] and was found in 8 of 1,345 individuals (0.6%) of Ashkenazi descent with colorectal cancer. Rare in the general population, the A636P mutation is detected in up to 7% of Ashkenazi Jewish patients with early age-of-onset colorectal cancer, and may account for up to one third of Lynch Syndrome in the Ashkenazi Jewish population.[5]. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available
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