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A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States

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A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States ORIGINAL CONTRIBUTION A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States Henry T. Lynch, MD Context Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Stephanie M. Coronel, MPH syndrome, is caused by mutations in the mismatch repair genes and confers an ex- Ross Okimoto, BS traordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical sur- Heather Hampel, MS, CGC veillance, at present the mutations are not tested for in mutation analyses. Kevin Sweet, MS, CGC Objective To describe the prevalence of a large genomic deletion encompassing ex- Jane F. Lynch, BSN ons1to6oftheMSH2 gene that is widespread in the US population as a result of a founder effect. Ali Barrows, BS Design, Setting, and Patients Ongoing genealogical and historical study con- Juul Wijnen, PhD ducted to assess the origin and spread of an MSH2 mutation previously identified in 9 Heleen van der Klift, MS apparently unrelated families with putative HNPCC and living in widely different geo- graphic locations in the United States. Patrick Franken, HLO Main Outcome Measures Classification of family members as carriers or noncar- Anja Wagner, PhD, MD riers of the MSH2 mutation; spread of the mutation across the continental United Riccardo Fodde, PhD States. Albert de la Chapelle, MD, PhD Results To date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mu- HE ANNUAL WORLDWIDE INCI- tation. Three families have been genealogically shown to descend from a German im- dence of colorectal cancer is es- migrant family that arrived and first settled in Pennsylvania in the early 1700s. Move- timated at 944717 cases,1 of ments of branches of the family from Pennsylvania through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah, Texas, and California have been docu- which about 10% (94472 cases) mented, and carriers of the mutation have already been diagnosed in 14 states. In Tare estimated to be hereditary.2,3 Heredi- contrast, the deletion was not found among 407 European and Australian families with tary nonpolyposis colorectal cancer HNPCC. (HNPCC), also known as Lynch syn- Conclusion The postulated high frequency and continent-wide geographic distri- drome, is the most common form of he- bution of a cancer-predisposing founder mutation of the MSH2 gene in a large, out- reditary colorectal cancer, accounting for bred (as opposed to genetically isolated) population, and the ease with which the mu- somewhere between 2% (18900 cases) tation can be detected, suggest that the routine testing of individuals at risk for HNPCC and 7% (66130 cases) of the annual in the United States should include an assay for this mutation until more is learned worldwide incidence of colorectal about its occurrence. cancer.4 JAMA. 2004;291:718-724 www.jama.com Most tumors from patients with HNPCC harbor a characteristic abnor- mality of an instability at short tandem- Author Affiliations: Department of Preventive Department of Clinical Genetics, Erasmus University Medicine, Creighton University School of Medicine, Medical Centre, Rotterdam, the Netherlands (Dr repeat sequences, ie, microsatellites, in Omaha, Neb (Dr H. T. Lynch; Mss Coronel, J. F. Wagner). Mr Franken and Dr Fodde are currently the genome.5-7 Cancer susceptibility in Lynch, and Barrows; and Mr Okimoto); Human Can- affiliated with the Department of Pathology, Jose- cer Genetics Program, Comprehensive Cancer Cen- phine Nefkens Institute, Erasmus University Medical patients with HNPCC is believed to be ter, The Ohio State University, Columbus (Ms Ham- Centre. caused by malfunction of postreplica- pel, Mr Sweet, and Dr de la Chapelle); Department Corresponding Author: Henry T. Lynch, MD, De- of Human Genetics, Sylvius Laboratory, Leiden Uni- partment of Preventive Medicine, Creighton Univer- tive mismatch repair, as evidenced by in- versity, Leiden, the Netherlands (Drs Wijnen and sity School of Medicine, 2500 California Plaza, Omaha, herited mutations in 1 of 5 different mis- Fodde, Ms van der Klift, and Mr Franken); and NE 68178 ([email protected]). 718 JAMA, February 11, 2004—Vol 291, No. 6 (Reprinted) ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 MSH2 MUTATION AND HEREDITARY NONPOLYPOSIS COLORECTAL CANCER match repair genes: MSH2, MLH1, of 1:10 at the founding increases or de- the screening of an additional cohort of MSH6, MLH3, and PMS2. More than 400 creases, or perhaps remains un- 11 families with HNPCC from Ohio State different pathogenic mutations have changed. The more isolated the popu- University’s resource, where this dele- been registered in the international da- lation, the more pronounced will be the tion was identified in 2 additional cases.26 tabase of mutations in HNPCC kin- effects of genetic drift. For these rea- Because of the extremely high risk for co- dreds (available at http://www.nfdht sons most founder mutations of this lorectal (80%-85%), endometrial (56%), .nl). Detection of mutations is usually type have been described in popula- ovarian (12%), and a number of other performed by sequencing. In the con- tions that have remained isolated while cancers in patients with HNPCC, it is de- text of the present report it is notewor- growing rapidly. Prime examples are the sirable to diagnose carriers of these mu- thy that by sequencing and other com- Finns (“founded” [ie, the main bottle- tations in order to identify high-risk in- monly used genetic testing methods, 1 neck occurred] approximately 2000 dividuals needing targeted clinical class of mutations, ie, large structural re- years ago13), Icelanders (approxi- surveillance. Our purpose is to describe arrangements such as large deletions, is mately 1100 years ago14), Ashkenazi the existence of a mutation that is wide- difficult to detect. These mutations can Jews (600-800 years ago15), and French spread in the US population as a result be readily detected by Southern hybrid- Canadians and Amish (250-400 years of a founder effect and its implications ization,8 multiplex ligation-dependent ago16). Hereditary breast cancer in the for the early detection and prevention of probe amplification,9 and after conver- Ashkenazi Jews, with cancer-predis- cancers associated with HNPCC. sion to haploidy.10,11 posing founder mutations in BRCA1 Among patients who meet the diag- (185delAG and 5382insC) and BRCA2 METHODS nostic criteria for HNPCC, about 40% to (6174delT), is a recent well-published This study was approved by the insti- 60% test positive for mutation, demon- example of a founder effect.17,18 tutional review boards of Creighton strated by a germline mutation in 1 of the At least 5 examples of founder muta- University and the Ohio State Univer- DNA mismatch repair genes; more than tions have been described in cases with sity. Family members provided in- 90% of these mutations are in MLH1 or HNPCC. In Finns, a 3.5-kilobase (kb) de- formed consent for separate institu- MSH2, while approximately 10% are letion of MLH1 comprising exon 16 ac- tional review board–approved colon MSH6 mutations.12 Up to 15% of all dis- counts for as many as half of all cases of cancer genetics studies at each partici- ease-causing mutations in patients with HNPCC, and a splice-site mutation af- pating institution. Genealogical, medi- HNPCC are believed to be large dele- fecting exon 6 of MLH1 accounts for 15% cal, and pathological reports were col- tions, especially in MSH2.8 to 20% of all cases.19 A splice-site muta- lected for members of the 9 extended A founder mutation arises in a single tion affecting exon 5 of MSH2 was first families over a period of more than 30 individual whose offspring each have detected in a large kindred in Newfound- years. Each family displayed inherit- a 50% chance of inheriting the muta- land20 and later turned out to be wide- ance patterns of cancer consonant with tion. The fate of the mutation in the spread in that population through a HNPCC, in concert with the presence subsequent generations will depend on founder effect.21 Interestingly, this mu- of the mutation. 2 main factors, namely, selection and tation has been observed in many other chance. If the mutation leads to selec- populations as well, and actually arises Genealogical Studies tive advantage, it may increase in fre- de novo with appreciable frequency22,23; Available key family members from quency. If it leads to selective disad- thus, this mutation is a recurrent one each of these mutation-verified HNPCC vantage, eg, reduced reproduction, it worldwide but its spread in Newfound- families were personally interviewed may disappear. land is by the founder mechanism. A when possible and/or completed de- In the absence of selection, chance nonsense mutation leading to a stop tailed family history questionnaires. In events known as genetic drift can codon in exon 19 of MLH1 is wide- order to decipher the relationships greatly influence its prevalence in the spread in the Valais region of Switzer- among the 9 families, genealogical re- population. Typically the incidence of land.24 A fifth founder mutation, cords from 3 databases were inten- founder mutations can be increased at 1906G→CinMSH2, is a major contribu- sively searched: the Church of Jesus population bottlenecks. If, for in- tor to HNPCC in the Ashkenazi Jewish Christ of Latter-Day Saints Family His- stance, a mutation occurs with a low in- population, where it may account for as torical Library, Ancestry.com, and a cidence (eg, 1:1000) in a mixed popu- many as one third of all cases.25 German family genealogy database. lation, and if 10 people were to emigrate The identification of a deletion en- These databases contained informa- from this population to an uninhab- compassing exons 1 to 6 of the MSH2 tion from individual family annals as ited island, and if 1 of the 10 were to gene in 7 seemingly unrelated families well as from federal and state census re- have the mutation, then a 100-fold en- with HNPCC from Creighton Universi- cords.
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