Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

Sanne W. ten Broeke*, Richard M. Brohet, Carli M. Tops, Heleen M. van der Klift, Mary E. Velthuizen, Inge Bernstein, Gabriel Capella Munar, Encarna Gomez Garcia, Nicoline Hoogerbrugge, Tom G. W. Letteboer, Fred H. Menko, Annika Lindblom, Arjen R. Mensenkamp, Pal Moller, Theo A. Van Os, Nils Rahner, Bert J. W. Redeker, Rolf H. Sijmons, Liesbeth Spruijt, Manon SuerinkYvonne J. Vos, Anja Wagner, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, Juul T. Wijnen

*Corresponding author for this work

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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.


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.


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.


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. (C) 2014 by American Society of Clinical Oncology

Original languageEnglish
Pages (from-to)319-325
Number of pages7
JournalJournal of Clinical Oncology
Issue number4
Publication statusPublished - 1-Feb-2015


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