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Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.
J Clin Oncol 2005; 23(27):6524-32JC

Abstract

PURPOSE

The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis.

METHODS

We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins.

RESULTS

Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%.

CONCLUSIONS

Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Authors+Show Affiliations

Genetic Epidemiology Laboratory, Department of Pathology, Australia.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 availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16116158

Citation

Southey, Melissa C., et al. "Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-onset Colorectal Cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 23, no. 27, 2005, pp. 6524-32.
Southey MC, Jenkins MA, Mead L, et al. Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol. 2005;23(27):6524-32.
Southey, M. C., Jenkins, M. A., Mead, L., Whitty, J., Trivett, M., Tesoriero, A. A., ... Hopper, J. L. (2005). Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 23(27), pp. 6524-32.
Southey MC, et al. Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-onset Colorectal Cancer. J Clin Oncol. 2005 Sep 20;23(27):6524-32. PubMed PMID: 16116158.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. AU - Southey,Melissa C, AU - Jenkins,Mark A, AU - Mead,Leeanne, AU - Whitty,Jonathan, AU - Trivett,Melanie, AU - Tesoriero,Andrea A, AU - Smith,Letitia D, AU - Jennings,Kim, AU - Grubb,Garry, AU - Royce,Simon G, AU - Walsh,Michael D, AU - Barker,Melissa A, AU - Young,Joanne P, AU - Jass,Jeremy R, AU - St John,D James B, AU - Macrae,Finlay A, AU - Giles,Graham G, AU - Hopper,John L, Y1 - 2005/08/22/ PY - 2005/8/24/pubmed PY - 2005/10/28/medline PY - 2005/8/24/entrez SP - 6524 EP - 32 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 23 IS - 27 N2 - PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC. SN - 0732-183X UR - https://www.unboundmedicine.com/medline/citation/16116158/Use_of_molecular_tumor_characteristics_to_prioritize_mismatch_repair_gene_testing_in_early_onset_colorectal_cancer_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2005.04.671?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -