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

J Clin Oncol 2015 Feb 15;33(4):319-25. Epub 2014 Dec 15.

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.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.57.8088DOI Listing
February 2015

Publication Analysis

Top Keywords

pms2 mutation
12
family members
8
mutation carriers
8
age crc
8
range years
8
years range
8
cancer risk
8
cancer risks
8
cancer
7
years
6
crc
6
pms2
6
mutation
5
risks
5
years 19%
4
age years
4
crc male
4
cumulative risk
4
risk crc
4
19% female
4

Similar Publications

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

Gastroenterology 2008 Aug 2;135(2):419-28. Epub 2008 May 2.

Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

Background & Aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Read More

View Article and Full-Text PDF
August 2008

Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome.

J Natl Cancer Inst 2013 Feb 5;105(4):274-9. Epub 2013 Feb 5.

Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, Level 3, 207 Bouverie St, University of Melbourne, VIC 3010 Australia.

Background: Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations. Read More

View Article and Full-Text PDF
February 2013

Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

Gastroenterology 2015 Nov 3;149(6):1446-53. Epub 2015 Aug 3.

Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois. Electronic address:

Background & Aims: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. Read More

View Article and Full-Text PDF
November 2015

Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome.

J Natl Cancer Inst 2012 Sep 28;104(18):1363-72. Epub 2012 Aug 28.

Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, Level 3, 207 Bouverie Street, The University of Melbourne, VIC 3010, Australia.

Background: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.

Methods: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. Read More

View Article and Full-Text PDF
September 2012