Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes
AuthorMead, LJ; Jenkins, MA; Young, J; Royce, SG; Smith, L; John, DJBS; Macrae, F; Giles, GG; Hopper, JL; Southey, MC
Source TitleClinical Cancer Research
PublisherAMER ASSOC CANCER RESEARCH
University of Melbourne Author/sJenkins, Mark; Royce, Simon; St John, Donald; Macrae, Finlay; Southey, Melissa; Hopper, John; MEAD, LEEANNE; SMITH, LETITIA; Giles, Graham
Document TypeJournal Article
CitationsMead, L. J., Jenkins, M. A., Young, J., Royce, S. G., Smith, L., John, D. J. B. S., Macrae, F., Giles, G. G., Hopper, J. L. & Southey, M. C. (2007). Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. CLINICAL CANCER RESEARCH, 13 (10), pp.2865-2869. https://doi.org/10.1158/1078-0432.CCR-06-2174.
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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 (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-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 (10)MSI-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 (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-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.
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