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High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation.
Gastroenterology 2011; 140(7):1919-26G

Abstract

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+Show Affiliations

Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21419771

Citation

Mukherjee, Bhramar, et al. "High Risk of Colorectal and Endometrial Cancer in Ashkenazi Families With the MSH2 A636P Founder Mutation." Gastroenterology, vol. 140, no. 7, 2011, pp. 1919-26.
Mukherjee B, Rennert G, Ahn J, et al. High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. Gastroenterology. 2011;140(7):1919-26.
Mukherjee, B., Rennert, G., Ahn, J., Dishon, S., Lejbkowicz, F., Rennert, H. S., ... Gruber, S. B. (2011). High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. Gastroenterology, 140(7), pp. 1919-26. doi:10.1053/j.gastro.2011.02.071.
Mukherjee B, et al. High Risk of Colorectal and Endometrial Cancer in Ashkenazi Families With the MSH2 A636P Founder Mutation. Gastroenterology. 2011;140(7):1919-26. PubMed PMID: 21419771.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. AU - Mukherjee,Bhramar, AU - Rennert,Gad, AU - Ahn,Jaeil, AU - Dishon,Sara, AU - Lejbkowicz,Flavio, AU - Rennert,Hedy S, AU - Shiovitz,Stacey, AU - Moreno,Victor, AU - Gruber,Stephen B, Y1 - 2011/03/16/ PY - 2010/11/12/received PY - 2011/02/08/revised PY - 2011/02/23/accepted PY - 2011/3/23/entrez PY - 2011/3/23/pubmed PY - 2011/8/10/medline SP - 1919 EP - 26 JF - Gastroenterology JO - Gastroenterology VL - 140 IS - 7 N2 - 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/21419771/High_risk_of_colorectal_and_endometrial_cancer_in_Ashkenazi_families_with_the_MSH2_A636P_founder_mutation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(11)00321-0 DB - PRIME DP - Unbound Medicine ER -