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.
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.
Authors: Christine M van Vliet; James G Dowty; Jane L van Vliet; Letitia Smith; Leeanne J Mead; Finlay A Macrae; D James B St John; Graham G Giles; Melissa C Southey; Mark A Jenkins; Gary M Velan; John L Hopper Journal: Hum Mutat Date: 2011-01-25 Impact factor: 4.878
Authors: S G Royce; K Alsop; A Haydon; L Mead; L D Smith; A A Tesoriero; G G Giles; M A Jenkins; J L Hopper; M C Southey Journal: Colorectal Dis Date: 2009-01-27 Impact factor: 3.788
Authors: Karen Curtin; Wade S Samowitz; Roger K Wolff; Bette J Caan; Cornelia M Ulrich; John D Potter; Martha L Slattery Journal: Mol Carcinog Date: 2009-11 Impact factor: 4.784
Authors: Bryony A Thompson; Amanda B Spurdle; John-Paul Plazzer; Marc S Greenblatt; Kiwamu Akagi; Fahd Al-Mulla; Bharati Bapat; Inge Bernstein; Gabriel Capellá; Johan T den Dunnen; Desiree du Sart; Aurelie Fabre; Michael P Farrell; Susan M Farrington; Ian M Frayling; Thierry Frebourg; David E Goldgar; Christopher D Heinen; Elke Holinski-Feder; Maija Kohonen-Corish; Kristina Lagerstedt Robinson; Suet Yi Leung; Alexandra Martins; Pal Moller; Monika Morak; Minna Nystrom; Paivi Peltomaki; Marta Pineda; Ming Qi; Rajkumar Ramesar; Lene Juel Rasmussen; Brigitte Royer-Pokora; Rodney J Scott; Rolf Sijmons; Sean V Tavtigian; Carli M Tops; Thomas Weber; Juul Wijnen; Michael O Woods; Finlay Macrae; Maurizio Genuardi Journal: Nat Genet Date: 2013-12-22 Impact factor: 38.330