Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer Journal Article

Authors: Latham, A.; Srinivasan, P.; Kemel, Y.; Shia, J.; Bandlamudi, C.; Mandelker, D.; Middha, S.; Hechtman, J.; Zehir, A.; Dubard-Gault, M.; Tran, C.; Stewart, C.; Sheehan, M.; Penson, A.; DeLair, D.; Yaeger, R.; Vijai, J.; Mukherjee, S.; Galle, J.; Dickson, M. A.; Janjigian, Y.; O’Reilly, E. M.; Segal, N.; Saltz, L. B.; Reidy-Lagunes, D.; Varghese, A. M.; Bajorin, D.; Carlo, M. I.; Cadoo, K.; Walsh, M. F.; Weiser, M.; Aguilar, J. G.; Klimstra, D. S.; Diaz, L. A. Jr; Baselga, J.; Zhang, L.; Ladanyi, M.; Hyman, D. M.; Solit, D. B.; Robson, M. E.; Taylor, B. S.; Offit, K.; Berger, M. F.; Stadler, Z. K.
Article Title: Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer
Abstract: PURPOSE Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)–associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively (P, .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases. CONCLUSION MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history. © 2018 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 37
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2019-02-01
Start Page: 286
End Page: 295
Language: English
DOI: 10.1200/jco.18.00283
PUBMED: 30376427
PROVIDER: scopus
PMCID: PMC6553803
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Dean Bajorin
    567 Bajorin
  2. Kenneth Offit
    668 Offit
  3. Leonard B Saltz
    703 Saltz
  4. Mark E Robson
    535 Robson
  5. David Solit
    622 Solit
  6. Neil Howard Segal
    156 Segal
  7. Liying Zhang
    120 Zhang
  8. Zsofia Kinga Stadler
    249 Stadler
  9. Diane Lauren Reidy
    226 Reidy
  10. Yelena Yuriy Janjigian
    231 Janjigian
  11. David S Klimstra
    945 Klimstra
  12. Marc Ladanyi
    1129 Ladanyi
  13. Jinru Shia
    581 Shia
  14. Martin R Weiser
    405 Weiser
  15. Rona Denit Yaeger
    158 Yaeger
  16. David Hyman
    345 Hyman
  17. Ahmet Zehir
    272 Zehir
  18. Mark Andrew Dickson
    115 Dickson
  19. Eileen O'Reilly
    514 O'Reilly
  20. Vijai Joseph
    167 Joseph
  21. Michael Forman Berger
    564 Berger
  22. Deborah F DeLair
    103 DeLair
  23. Barry Stephen Taylor
    224 Taylor
  24. Yelena Kemel
    47 Kemel
  25. Karen Anne Cadoo
    91 Cadoo
  26. Maria Isabel Carlo
    77 Carlo
  27. Jose T Baselga
    480 Baselga
  28. Jaclyn Frances Hechtman
    193 Hechtman
  29. Margaret Rebecca Graham Sheehan
    17 Sheehan
  30. Michael Francis Walsh
    95 Walsh
  31. Sumit   Middha
    81 Middha
  32. Jesse   Galle
    8 Galle
  33. Alexander Vincent Penson
    39 Penson
  34. Christina Tran
    12 Tran
  35. Luis Alberto Diaz
    76 Diaz