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Microsatellite Instability Markers for Identifying Early-Onset Colorectal Cancers Caused by Germ-Line Mutations in DNA Mismatch Repair Genes

Authors' Affiliations: ¹ Genetic Epidemiology Laboratory, Department of Pathology and ² Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne; ³ Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital; ⁴ Centre for Cancer Epidemiology, The Cancer Council Victoria, Melbourne, Victoria, Australia; ⁵ Molecular Cancer Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia; and ⁶ The IARC, Lyon, France

Requests for reprints: John L. Hopper, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, 3010 Australia. Phone: 61-3-8344-0697; Fax: 61-3-9347-9824; E-mail: j.hopper{at}unimelb.edu.au

Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes.

Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel.

Results: The National Cancer Institute five-marker panel system scored 31 (29%) as ^NCIMSI-High, 13 (12%) as ^NCIMSI-Low, and 63 (59%) as ^NCIMS-Stable. The 10-marker panel classified 18 (17%) as ¹⁰MSI-High, 17 (16%) as ¹⁰MSI-Low, and 72 (67%) as ¹⁰MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all ¹⁰MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored ¹⁰MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored ¹⁰MSI-High).

Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.