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Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics

Robinson, Kristina Lagerstedt; Liu, Tao; Vandrovcova, Jana; Halvarsson, Britta LU ; Clendenning, Mark; Frebourg, Thierry; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert and Peltomaki, Paivi, et al. (2007) In Journal of the National Cancer Institute 99(4). p.291-299
Abstract
Background Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a... (More)
Background Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. Results Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. Conclusion Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with IVISI-negative tumors. (Less)
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publication status
published
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Journal of the National Cancer Institute
volume
99
issue
4
pages
291 - 299
publisher
Oxford University Press
external identifiers
  • wos:000244523800009
  • scopus:33847794097
ISSN
1460-2105
DOI
10.1093/jnci/djk051
language
English
LU publication?
yes
id
07abb9c4-8fe2-45f4-b133-bb08ec3ffd87 (old id 673622)
date added to LUP
2007-12-14 12:21:22
date last changed
2017-10-01 04:43:41
@article{07abb9c4-8fe2-45f4-b133-bb08ec3ffd87,
  abstract     = {Background Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. Results Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. Conclusion Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with IVISI-negative tumors.},
  author       = {Robinson, Kristina Lagerstedt and Liu, Tao and Vandrovcova, Jana and Halvarsson, Britta and Clendenning, Mark and Frebourg, Thierry and Papadopoulos, Nickolas and Kinzler, Kenneth W. and Vogelstein, Bert and Peltomaki, Paivi and Kolodner, Richard D. and Nilbert, Mef and Lindblom, Annika},
  issn         = {1460-2105},
  language     = {eng},
  number       = {4},
  pages        = {291--299},
  publisher    = {Oxford University Press},
  series       = {Journal of the National Cancer Institute},
  title        = {Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics},
  url          = {http://dx.doi.org/10.1093/jnci/djk051},
  volume       = {99},
  year         = {2007},
}