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Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.
J Natl Cancer Inst 2007; 99(4):291-9JNCI

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 MSI-negative tumors.

Authors+Show Affiliations

Department of Clinical Genetics, Karolinska University Hospital, S-17176 Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17312306

Citation

Lagerstedt Robinson, Kristina, et al. "Lynch Syndrome (hereditary Nonpolyposis Colorectal Cancer) Diagnostics." Journal of the National Cancer Institute, vol. 99, no. 4, 2007, pp. 291-9.
Lagerstedt Robinson K, Liu T, Vandrovcova J, et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst. 2007;99(4):291-9.
Lagerstedt Robinson, K., Liu, T., Vandrovcova, J., Halvarsson, B., Clendenning, M., Frebourg, T., ... Lindblom, A. (2007). Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. Journal of the National Cancer Institute, 99(4), pp. 291-9.
Lagerstedt Robinson K, et al. Lynch Syndrome (hereditary Nonpolyposis Colorectal Cancer) Diagnostics. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9. PubMed PMID: 17312306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. AU - Lagerstedt Robinson,Kristina, AU - Liu,Tao, AU - Vandrovcova,Jana, AU - Halvarsson,Britta, AU - Clendenning,Mark, AU - Frebourg,Thierry, AU - Papadopoulos,Nickolas, AU - Kinzler,Kenneth W, AU - Vogelstein,Bert, AU - Peltomäki,Päivi, AU - Kolodner,Richard D, AU - Nilbert,Mef, AU - Lindblom,Annika, PY - 2007/2/22/pubmed PY - 2007/3/14/medline PY - 2007/2/22/entrez SP - 291 EP - 9 JF - Journal of the National Cancer Institute JO - J. Natl. Cancer Inst. VL - 99 IS - 4 N2 - 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 MSI-negative tumors. SN - 1460-2105 UR - https://www.unboundmedicine.com/medline/citation/17312306/Lynch_syndrome__hereditary_nonpolyposis_colorectal_cancer__diagnostics_ L2 - https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djk051 DB - PRIME DP - Unbound Medicine ER -