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Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.
Gut. 2006 Dec; 55(12):1781-8.Gut

Abstract

BACKGROUND

Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations.

AIM

To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients.

METHODS

In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours.

RESULTS

25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years.

CONCLUSION

Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

Authors+Show Affiliations

Department of Gastroenterology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.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

Language

eng

PubMed ID

16636019

Citation

Niessen, R C., et al. "Identification of Mismatch Repair Gene Mutations in Young Patients With Colorectal Cancer and in Patients With Multiple Tumours Associated With Hereditary Non-polyposis Colorectal Cancer." Gut, vol. 55, no. 12, 2006, pp. 1781-8.
Niessen RC, Berends MJ, Wu Y, et al. Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. Gut. 2006;55(12):1781-8.
Niessen, R. C., Berends, M. J., Wu, Y., Sijmons, R. H., Hollema, H., Ligtenberg, M. J., de Walle, H. E., de Vries, E. G., Karrenbeld, A., Buys, C. H., van der Zee, A. G., Hofstra, R. M., & Kleibeuker, J. H. (2006). Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. Gut, 55(12), 1781-8.
Niessen RC, et al. Identification of Mismatch Repair Gene Mutations in Young Patients With Colorectal Cancer and in Patients With Multiple Tumours Associated With Hereditary Non-polyposis Colorectal Cancer. Gut. 2006;55(12):1781-8. PubMed PMID: 16636019.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. AU - Niessen,R C, AU - Berends,M J W, AU - Wu,Y, AU - Sijmons,R H, AU - Hollema,H, AU - Ligtenberg,M J L, AU - de Walle,H E K, AU - de Vries,E G E, AU - Karrenbeld,A, AU - Buys,C H C M, AU - van der Zee,A G J, AU - Hofstra,R M W, AU - Kleibeuker,J H, Y1 - 2006/04/24/ PY - 2006/4/26/pubmed PY - 2007/1/4/medline PY - 2006/4/26/entrez SP - 1781 EP - 8 JF - Gut JO - Gut VL - 55 IS - 12 N2 - BACKGROUND: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations. AIM: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients. METHODS: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours. RESULTS: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years. CONCLUSION: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion. SN - 0017-5749 UR - https://www.unboundmedicine.com/medline/citation/16636019/Identification_of_mismatch_repair_gene_mutations_in_young_patients_with_colorectal_cancer_and_in_patients_with_multiple_tumours_associated_with_hereditary_non_polyposis_colorectal_cancer_ L2 - https://gut.bmj.com/lookup/pmidlookup?view=long&pmid=16636019 DB - PRIME DP - Unbound Medicine ER -