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Cited by 1,408Genetic factors in colorectal cancerBRCA gene mutations in cancerColorectal Cancer Screening and Detection

Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)

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Hampel, Heather, Frankel, Wendy L., Martin, Edward, Arnold, Mark, Khanduja, Karamjit, Kuebler, Philip, Nakagawa, Hidewaki, Sotamaa, Kaisa +7 more·2005·New England Journal of Medicine
DOI 10.1056/nejmoa043146
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Abstract

BACKGROUND: Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome. METHODS: Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. RESULTS: Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not. CONCLUSIONS: Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.

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  • The vast majority of Lynch syndrome-associated colorectal cancers show loss of immunostaining for at least 1 of the gene products and are microsatellite unstable.

    “The vast majority of Lynch syndrome-associated colorectal cancers show loss of immunostaining for at least 1 of the gene products and are microsatellite unstable (59).”

    From Adrenocortical carcinoma (2014) · cites this paper as [59]

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Authors
Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., Nakagawa, H., Sotamaa, K., Prior, T. W., Westman, J., Panescu, J., Fix, D., Lockman, J., Comeras, I., & de la Chapelle, A.
Affiliations
  • The Ohio State University (US)
  • Mount Carmel Health (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2005-05-05
Volume
352
Issue
18
Pages
1851-1860
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa043146
OpenAlex
W2112565258
Cited by
1,408
References
35
Citations by year
2026: 34 · 2025: 40 · 2024: 41 · 2023: 64 · 2022: 57 · 2021: 86 · 2020: 68 · 2019: 77 · 2018: 87 · 2017: 58 · 2016: 75 · 2015: 74 · 2014: 79 · 2013: 81 · 2012: 66
FWCI
47.46
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (CA67941, CA16058, P30CA016058)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Screening and Detection
Keywords
Lynch syndrome, microsatellite instability, mismatch repair genes, MLH1, MSH2, MSH6, PMS2, immunohistochemical screening, colorectal adenocarcinoma, family screening, mutation testing, Amsterdam criteria, Bethesda guidelines
MeSH terms
MutL Protein Homolog 1, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Carrier Proteins, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mutational Analysis, DNA Repair, Electrophoresis, Female, Genotype, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Proteins, Nuclear Proteins, Promoter Regions, Genetic, Colorectal Neoplasms, Germ-Line Mutation, Microsatellite Repeats, DNA Methylation, Base Pair Mismatch, Genomic Instability, Adaptor Proteins, Signal Transducing

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