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2754059 
Journal Article 
Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk 
Ten Broeke, SW; Brohet, RM; Tops, CM; van Der Klift, HM; Velthuizen, ME; Bernstein, I; Capellá Munar, G; Gomez Garcia, E; Hoogerbrugge, N; Letteboer, TG; Menko, FH; Lindblom, A; Mensenkamp, AR; Moller, P; van Os, TA; Rahner, N; Redeker, BJ; Sijmons, RH; Spruijt, L; Suerink, M; Vos, YJ; Wagner, A; Hes, FJ; Vasen, HF; Nielsen, M; Wijnen, JT 
2014 
Yes 
Journal of Clinical Oncology
ISSN: 0732-183X
EISSN: 1527-7755 
33 
319-325 
English 
PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.

METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.

RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.

CONCLUSION: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.