TY - JOUR
T1 - Lynch Syndrome Caused by Germline PMS2 Mutations
T2 - Delineating the Cancer Risk
AU - Ten Broeke, Sanne W
AU - Brohet, Richard M
AU - Tops, Carli M
AU - van der Klift, Heleen M
AU - Velthuizen, Mary E
AU - Bernstein, Inge
AU - Capellá Munar, Gabriel
AU - Gomez Garcia, Encarna
AU - Hoogerbrugge, Nicoline
AU - Letteboer, Tom G W
AU - Menko, Fred H
AU - Lindblom, Annika
AU - Mensenkamp, Arjen R
AU - Moller, Pal
AU - van Os, Theo A
AU - Rahner, Nils
AU - Redeker, Bert J W
AU - Sijmons, Rolf H
AU - Spruijt, Liesbeth
AU - Suerink, Manon
AU - Vos, Yvonne J
AU - Wagner, Anja
AU - Hes, Frederik J
AU - Vasen, Hans F
AU - Nielsen, Maartje
AU - Wijnen, Juul T
N1 - © 2014 by American Society of Clinical Oncology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1200/JCO.2014.57.8088
DO - 10.1200/JCO.2014.57.8088
M3 - Journal article
C2 - 25512458
SN - 0732-183X
VL - 33
SP - 319
EP - 325
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 4
ER -