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Cancer genetics
Original article
HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer
  1. Olivier Buhard1,2,
  2. Anaïs Lagrange1,2,
  3. Agathe Guilloux1,2,3,
  4. Chrystelle Colas1,2,
  5. Mouna Chouchène1,2,
  6. Kristell Wanherdrick1,2,
  7. Florence Coulet1,2,
  8. Erell Guillerm1,2,
  9. Coralie Dorard1,2,
  10. Laetitia Marisa1,4,
  11. Adem Bokhari1,2,
  12. Malorie Greene1,2,
  13. Nizar El-Murr1,2,
  14. Sahra Bodo1,2,
  15. Martine Muleris1,2,
  16. Isabelle Sourouille1,2,
  17. Magali Svrcek1,2,5,
  18. Pascale Cervera1,2,5,
  19. Hélène Blanché6,
  20. Jérémie H Lefevre1,2,7,
  21. Yann Parc1,2,7,
  22. Come Lepage8,9,
  23. Caroline Chapusot8,9,
  24. Anne-Marie Bouvier8,9,
  25. Marie-Pierre Gaub10,
  26. Janick Selves11,
  27. Kerryn Garrett12,
  28. Barry Iacopetta13,
  29. Richie Soong14,
  30. Richard Hamelin1,2,
  31. Carmen Garrido9,15,
  32. Olivier Lascols2,16,
  33. Thierry André1,2,17,
  34. Jean-François Fléjou1,2,5,
  35. Ada Collura1,2,
  36. Alex Duval1,2
  1. 1INSERM, UMRS 938—Centre de Recherche Saint-Antoine, Equipe ‘Instabilité des Microsatellites et Cancers’, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France
  2. 2Université Pierre et Marie Curie, Paris, France
  3. 3Centre de Mathématiques Appliquées, Ecole Polytechnique and CNRS UMR 7641, 91128 Palaiseau, France
  4. 4Programme ‘Cartes d'Identité des Tumeurs’, Ligue Nationale Contre le Cancer, Paris, France
  5. 5AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France
  6. 6Fondation Jean Dausset-CEPH, Paris, France
  7. 7AP-HP, Service de Chirurgie Générale et Digestive, Hôpital Saint-Antoine, Paris, France
  8. 8Burgundy Cancer Registry, INSERM U866, Burgundy University, Dijon University Hospital, Dijon, France
  9. 9Faculty of Medicine, INSERM UMR 866, University of Burgundy, Dijon, France
  10. 10INSERM, U682, Développement et Physiopathologie de l'Intestin et du Pancréas, Strasbourg, France
  11. 11INSERM, Unité 563, Centre de Recherche sur le Cancer de Toulouse, France
  12. 12Bendat Family Comprehensive Cancer Centre, St John of God HealthCare, Subiaco, Australia
  13. 13School of Surgery M507, University of Western Australia, Nedlands, Australia
  14. 14Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
  15. 15Centre de lutte contre le cancer George-François Leclerc, Dijon, France
  16. 16AP-HP, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France
  17. 17AP-HP, Hôpital Saint-Antoine, Service d'oncologie médicale, Paris, France
  1. Correspondence to Dr Alex Duval, INSERM, UMRS 938—Centre de Recherche Saint-Antoine, Equipe ‘Instabilité des Microsatellites et Cancers’, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris F-75012, France; alex.duval{at}inserm.fr

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.

  • Cancer: colon
  • Genetics
  • Molecular genetics
  • Diagnosis
  • Colorectal cancer

https://doi.org/10.1136/jmedgenet-2015-103518

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