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Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency.
Colorectal Dis. 2008 Jun; 10(5):490-7.CD

Abstract

OBJECTIVE

Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice.

METHOD

Tumours and blood samples from 262 successive patients with colorectal adenocarcinomas were collected. Expression of the MMR proteins MLH1, MSH2, and MSH6 by immunohistochemistry (IHC) was compared with MSI DNA analysis. Methylation analysis of MLH1 and mutation analysis for BRAF V600E were compared in samples with MSI and/or lack of MLH1 expression to determine if the tumour was likely to be sporadic.

RESULTS

Thirty-nine (14.9%) of the tumours showed MMR deficiency by IHC or by microsatellite analysis. Sporadic inactivation by methylation of MLH1 promoter was found in 35 patients whereby the BRAF activating V600E mutation, indicating sporadic origin, was found in 32 tumours. On the basis of molecular characteristics we found 223 patients with intact MMR, 35 patients with sporadic MMR deficiency, and four patients who were likely to have hereditary MMR deficiency.

CONCLUSION

To obtain the maximal benefit for patients and clinicians, MMR testing should be supplemented with MLH1 methylation or BRAF mutation analysis to distinguish sporadic patients from likely hereditary ones. MMR deficient patients with sporadic disease can be reassured of the better prognosis and the likely hereditary cases should receive genetic counselling.

Authors+Show Affiliations

Danish Colorectal Cancer Group South, University of Southern Denmark and Vejle Hospital, Vejle, Denmark. laheje@vgs.vejleamt.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17868408

Citation

Jensen, L H., et al. "Strategy in Clinical Practice for Classification of Unselected Colorectal Tumours Based On Mismatch Repair Deficiency." Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland, vol. 10, no. 5, 2008, pp. 490-7.
Jensen LH, Lindebjerg J, Byriel L, et al. Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. Colorectal Dis. 2008;10(5):490-7.
Jensen, L. H., Lindebjerg, J., Byriel, L., Kolvraa, S., & Crüger, D. G. (2008). Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland, 10(5), 490-7.
Jensen LH, et al. Strategy in Clinical Practice for Classification of Unselected Colorectal Tumours Based On Mismatch Repair Deficiency. Colorectal Dis. 2008;10(5):490-7. PubMed PMID: 17868408.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. AU - Jensen,L H, AU - Lindebjerg,J, AU - Byriel,L, AU - Kolvraa,S, AU - Crüger,D G, Y1 - 2007/09/13/ PY - 2007/9/18/pubmed PY - 2008/7/22/medline PY - 2007/9/18/entrez SP - 490 EP - 7 JF - Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland JO - Colorectal Dis VL - 10 IS - 5 N2 - OBJECTIVE: Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice. METHOD: Tumours and blood samples from 262 successive patients with colorectal adenocarcinomas were collected. Expression of the MMR proteins MLH1, MSH2, and MSH6 by immunohistochemistry (IHC) was compared with MSI DNA analysis. Methylation analysis of MLH1 and mutation analysis for BRAF V600E were compared in samples with MSI and/or lack of MLH1 expression to determine if the tumour was likely to be sporadic. RESULTS: Thirty-nine (14.9%) of the tumours showed MMR deficiency by IHC or by microsatellite analysis. Sporadic inactivation by methylation of MLH1 promoter was found in 35 patients whereby the BRAF activating V600E mutation, indicating sporadic origin, was found in 32 tumours. On the basis of molecular characteristics we found 223 patients with intact MMR, 35 patients with sporadic MMR deficiency, and four patients who were likely to have hereditary MMR deficiency. CONCLUSION: To obtain the maximal benefit for patients and clinicians, MMR testing should be supplemented with MLH1 methylation or BRAF mutation analysis to distinguish sporadic patients from likely hereditary ones. MMR deficient patients with sporadic disease can be reassured of the better prognosis and the likely hereditary cases should receive genetic counselling. SN - 1463-1318 UR - https://www.unboundmedicine.com/medline/citation/17868408/Strategy_in_clinical_practice_for_classification_of_unselected_colorectal_tumours_based_on_mismatch_repair_deficiency_ L2 - https://doi.org/10.1111/j.1463-1318.2007.01378.x DB - PRIME DP - Unbound Medicine ER -