BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Authors: W D Foulkes; I Thiffault; S B Gruber; M Horwitz; N Hamel; C Lee; J Shia; A Markowitz; A Figer; E Friedman; D Farber; C M T Greenwood; J D Bonner; K Nafa; T Walsh; V Marcus; L Tomsho; J Gebert; F A Macrae; C L Gaff; B Bressac-De Paillerets; P K Gregersen; J N Weitzel; P H Gordon; E MacNamara; M-C King; H Hampel; A De La Chapelle; J Boyd; K Offit; G Rennert; G Chong; N A Ellis Journal: Am J Hum Genet Date: 2002-11-26 Impact factor: 11.025
Authors: L Raskin; F Schwenter; M Freytsis; M Tischkowitz; N Wong; G Chong; S A Narod; D A Levine; F Bogomolniy; M Aronson; S N Thibodeau; K S Hunt; G Rennert; S Gallinger; S B Gruber; W D Foulkes Journal: Clin Genet Date: 2010-12-14 Impact factor: 4.438
Authors: Tuan A Dinh; Benjamin I Rosner; James C Atwood; C Richard Boland; Sapna Syngal; Hans F A Vasen; Stephen B Gruber; Randall W Burt Journal: Cancer Prev Res (Phila) Date: 2010-11-18
Authors: Judith Balmaña; David H Stockwell; Ewout W Steyerberg; Elena M Stoffel; Amie M Deffenbaugh; Julia E Reid; Brian Ward; Thomas Scholl; Brant Hendrickson; John Tazelaar; Lynn Anne Burbidge; Sapna Syngal Journal: JAMA Date: 2006-09-27 Impact factor: 56.272
Authors: José G Guillem; Beth S Rapaport; Tomas Kirchhoff; Prema Kolachana; Khedoudja Nafa; Emily Glogowski; Rob Finch; Helen Huang; William D Foulkes; Arnold Markowitz; Nathan A Ellis; Kenneth Offit Journal: J Am Coll Surg Date: 2003-02 Impact factor: 6.113
Authors: H F Vasen; J T Wijnen; F H Menko; J H Kleibeuker; B G Taal; G Griffioen; F M Nagengast; E H Meijers-Heijboer; L Bertario; L Varesco; M L Bisgaard; J Mohr; R Fodde; P M Khan Journal: Gastroenterology Date: 1996-04 Impact factor: 22.682
Authors: Kelly L Stratton; Shaheen Alanee; Emily A Glogowski; Kasmintan A Schrader; Rohini Rau-Murthy; Robert Klein; Paul Russo; Jonathan Coleman; Kenneth Offit Journal: Urol Oncol Date: 2015-12-23 Impact factor: 3.498
Authors: Celine H M Leenen; Mariska den Heijer; Conny van der Meer; Ernst J Kuipers; Monique E van Leerdam; Anja Wagner Journal: Fam Cancer Date: 2016-01 Impact factor: 2.375