HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

作者：Olivier Buhard, Anaïs Lagrange, Agathe Guilloux, Chrystelle Colas, Mouna Chouchène, Kristell Wanherdrick, Florence Coulet, Erell Guillerm, Coralie Dorard, Laëtitia Marisa, A'Dem Bokhari, Malorie Greene, Nizar El-Murr, Sahra Bodo, Martine Muleris, Isabelle Sourouille, Magali Svrcek, Pascale Cervera, Hélène Blanché, Jérémie H. Lefèvre, Yann Parc, Côme Lepage, Caroline Chapusot, Anne‐Marie Bouvier, Marie-Pierre Gaub, Janick Sèlves, Kerryn L. Garrett, Barry Iacopetta, Richie Soong, Richard Hamelin, Carmen Garrido, Olivier Lascols, Thierry André, Jean–François Fléjou, Ada Collura, Alex Duval · 发表于：Journal of Medical Genetics · 年份：2016 · DOI：10.1136/jmedgenet-2015-103518 · 被引用次数：61 · 研究领域：Genetic factors in colorectal cancer、Blood disorders and treatments、Connective tissue disorders research

BACKGROUND: Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI, a marker for defective DNA mismatch repair) as a first screen for Lynch syndrome (LS). In this study, we investigated whether it may be possible to improve the detection of MSI in CRC. We examined whether the HT17 DNA repeat (critical for correct splicing of the chaperone HSP110) might constitute a superior marker for diagnosis of the MSI phenotype in patients with CRC compared with the standard panel of markers (pentaplex). METHODS: The HT17 polymorphism was analysed in germline DNA from 1037 multi-ethnic individuals. We assessed its sensitivity and specificity for detecting MSI in a multicentre, population-based cohort of 685 patients with CRC and an additional series of 70 patients with CRC considered to be at-risk of LS. All cases were screened earlier for MSI using pentaplex markers. Cases showing discordant HT17/pentaplex results were further examined for the expression of mismatch repair proteins. RESULTS: HT17 status was analysed independently and blinded to previous results from pentaplex genotyping. HT17 showed no germline allelic variation outside a very narrow range. Compared with the pentaplex panel, HT17 showed better sensitivity (0.984 (95% CI 0.968 to 0.995) vs 0.951 (95% CI 0.925 to 0.972)) and similar specificity (0.997 (95% CI 0.989 to 1.000) for both) for the detection of MSI. Furthermore, HT17 alone correctly classified samples judged to be uncertain wi...