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

Abstract

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 earlyonset 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. 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.

T[20] repeat in the 3′-untranslated region of the MT1X gene: a marker with high sensitivity and specificity to detect microsatellite instability in colorectal cancer

“…We decided to investigate the MSI profile of this new marker that we called MT1XT20, in a larger series of colorectal cancer cases. In comparison with previously suggested mononucleotide markers such as BAT25, BAT26, NR-21, NR-22, and NR-24 [17], in our series, MT1XT20 seems to possess very high sensitivity for detecting the MSI-H phenotype in colorectal cancer, very similar to those found for BAT26, CAT25 [15], and MybT22 [28]. Moreover, MT1XT20 revealed absolute specificity because we did not find microsatellite instability in MSS nor MSI-L cases for MT1XT20, as well as for CAT25 and MybT22.…”

Morphological predictors of BRCA1 germline mutations in young women with breast cancer

“…Therefore, our data suggest that is possible to institute a pathology-based and more sensitive and specific method for prioritising women with early-onset breast cancer for BRCA1 mutation testing, similar to that which already applies to colorectal cancer and the DNA mismatch repair genes (Boland et al , 1998; Vasen et al , 1999; Southey et al , 2005; Lenz, 2005; Mead et al , 2007). We intend to undertake an independent study to further improve our algorithms, and we encourage others to try to validate and extend this approach, especially to later-onset disease.…”

Preoperative Diagnosis of Lynch Syndrome With DNA Mismatch Repair Immunohistochemistry on a Diagnostic Biopsy

“…The presence of an MSH6 mutation can result in a MRD tumor with a low or normal MSI status. 4,20 The second patient had a 16 base pair deletion in the PMS2 gene (PMS2 c.736 -741del16ins11) which results in a truncated protein at amino acid 246. From the normal PMS2 MMR IHC result, it must be assumed that this truncated protein is stable and contains the epitope recognized by the ␣-PMS2 antibody used in the assay.…”