胚系 PMS2 突变导致的林奇综合征：明确癌症风险。

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

机构信息

Sanne W. ten Broeke, Carli M. Tops, Heleen M. van der Klift, Manon Suerink, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, and Juul T. Wijnen, Leiden University Medical Center; Hans F. Vasen, The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden; Richard M. Brohet, Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp; Mary E. Velthuizen and Tom G.W. Letteboer, University Medical Center Utrecht, Utrecht; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Fred H. Menko, Vrije Universiteit, University Medical Center; Theo A. van Os and Bert J.W. Redeker, Academic Medical Center, Amsterdam; Rolf H. Sijmons and Yvonne J. Vos, University of Groningen, University Medical Center Groningen, Groningen; Anja Wagner, Erasmus University Medical Center, Rotterdam, the Netherlands; Inge Bernstein, Aalborg University Hospital, Aalborg; Inge Bernstein, Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre University Hospital Copenhagen, Denmark; Gabriel Capellá Munar, Hereditary Cancer Program, Catalan Institute of Oncology-Institut D'Investigació Biomèdica de Bellvitge, l'Hospitalet de Llobregat, Spain; Annika Lindblom, Karolinska Institutet, Karolinska University Hospital, Solna; Pal Moller, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway; and Nils Rahner, Institute of Human Genetics, University of Dusseldorf, Dusseldorf, Germany.

出版信息

J Clin Oncol. 2015 Feb 1;33(4):319-25. doi: 10.1200/JCO.2014.57.8088. Epub 2014 Dec 15.

DOI:10.1200/JCO.2014.57.8088

PMID:25512458

Abstract

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.

摘要

目的

与其他林奇相关错配修复基因（MMR）突变相比，PMS2 种系突变的临床后果了解甚少。本项欧洲队列研究旨在定义 PMS2 突变携带者所面临的癌症风险。

方法

从 98 个来自家族癌症诊所的 PMS2 家系中收集数据，共包括 2548 名家族成员和 377 名已证实的突变携带者。为了调整潜在的检出偏倚，使用修正的分离分析模型来计算结直肠癌（CRC）和子宫内膜癌（EC）的风险。计算标准化发病比（SIR）以评估其他林奇综合征相关癌症的风险。

结果

70 岁时男性突变携带者的 CRC 累积风险（CR）为 19%。女性携带者的 CRC 风险为 11%，EC 风险为 12%。CRC 的平均发病年龄为 52 岁，且先证者（平均 47 岁；范围，26 岁至 68 岁）与携带 PMS2 突变的其他家族成员（平均 58 岁；范围，31 岁至 86 岁；P＜0.001）的 CRC 平均发病年龄存在显著差异。还观察到小肠、卵巢、乳腺和肾盂癌的 SIR 显著升高。