Olivier Buhard1, Anaïs Lagrange1, Agathe Guilloux2, Chrystelle Colas1, Mouna Chouchène1, Kristell Wanherdrick1, Florence Coulet1, Erell Guillerm1, Coralie Dorard1, Laetitia Marisa3, Adem Bokhari1, Malorie Greene1, Nizar El-Murr1, Sahra Bodo1, Martine Muleris1, Isabelle Sourouille1, Magali Svrcek4, Pascale Cervera4, Hélène Blanché5, Jérémie H Lefevre6, Yann Parc6, Come Lepage7, Caroline Chapusot7, Anne-Marie Bouvier7, Marie-Pierre Gaub8, Janick Selves9, Kerryn Garrett10, Barry Iacopetta11, Richie Soong12, Richard Hamelin1, Carmen Garrido13, Olivier Lascols14, Thierry André15, Jean-François Fléjou4, Ada Collura1, Alex Duval1. 1. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France. 2. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France Centre de Mathématiques Appliquées, Ecole Polytechnique and CNRS UMR 7641, 91128 Palaiseau, France. 3. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Programme 'Cartes d'Identité des Tumeurs', Ligue Nationale Contre le Cancer, Paris, France. 4. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. 5. Fondation Jean Dausset-CEPH, Paris, France. 6. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France AP-HP, Service de Chirurgie Générale et Digestive, Hôpital Saint-Antoine, Paris, France. 7. Burgundy Cancer Registry, INSERM U866, Burgundy University, Dijon University Hospital, Dijon, France Faculty of Medicine, INSERM UMR 866, University of Burgundy, Dijon, France. 8. INSERM, U682, Développement et Physiopathologie de l'Intestin et du Pancréas, Strasbourg, France. 9. INSERM, Unité 563, Centre de Recherche sur le Cancer de Toulouse, France. 10. Bendat Family Comprehensive Cancer Centre, St John of God HealthCare, Subiaco, Australia. 11. School of Surgery M507, University of Western Australia, Nedlands, Australia. 12. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. 13. Faculty of Medicine, INSERM UMR 866, University of Burgundy, Dijon, France Centre de lutte contre le cancer George-François Leclerc, Dijon, France. 14. Université Pierre et Marie Curie, Paris, France AP-HP, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France. 15. INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France AP-HP, Hôpital Saint-Antoine, Service d'oncologie médicale, Paris, France.
Abstract
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 with the pentaplex panel and showed excellent ability to detect MSI in patients with LS. CONCLUSIONS: HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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 with the pentaplex panel and showed excellent ability to detect MSI in patients with LS. CONCLUSIONS: HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Ioannis Ladas; Fangyan Yu; Ka Wai Leong; Mariana Fitarelli-Kiehl; Chen Song; Ravina Ashtaputre; Matthew Kulke; Harvey Mamon; G Mike Makrigiorgos Journal: Nucleic Acids Res Date: 2018-07-06 Impact factor: 16.971
Authors: Antoine Daunay; Alex Duval; Laura G Baudrin; Olivier Buhard; Victor Renault; Jean-François Deleuze; Alexandre How-Kit Journal: Nucleic Acids Res Date: 2019-12-02 Impact factor: 16.971