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
DOI/URL:
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
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MSK Authors
  1. Dean Bajorin
    637 Bajorin
  2. Kenneth Offit
    764 Offit
  3. Leonard B Saltz
    760 Saltz
  4. Mark E Robson
    644 Robson
  5. David Solit
    729 Solit
  6. Neil Howard Segal
    189 Segal
  7. Anna Mary Varghese
    126 Varghese
  8. Liying Zhang
    128 Zhang
  9. Zsofia Kinga Stadler
    361 Stadler
  10. Diane Lauren Reidy
    280 Reidy
  11. Yelena Yuriy Janjigian
    349 Janjigian
  12. David S Klimstra
    976 Klimstra
  13. Marc Ladanyi
    1277 Ladanyi
  14. Jinru Shia
    667 Shia
  15. Martin R Weiser
    490 Weiser
  16. Rona Denit Yaeger
    263 Yaeger
  17. David Hyman
    352 Hyman
  18. Ahmet Zehir
    336 Zehir
  19. Mark Andrew Dickson
    154 Dickson
  20. Eileen O'Reilly
    679 O'Reilly
  21. Vijai Joseph
    204 Joseph
  22. Michael Forman Berger
    701 Berger
  23. Deborah F DeLair
    105 DeLair
  24. Barry Stephen Taylor
    236 Taylor
  25. Yelena Kemel
    93 Kemel
  26. Karen Anne Cadoo
    109 Cadoo
  27. Maria Isabel Carlo
    141 Carlo
  28. Jose T Baselga
    483 Baselga
  29. Jaclyn Frances Hechtman
    208 Hechtman
  30. Margaret Rebecca Graham Sheehan
    42 Sheehan
  31. Michael Francis Walsh
    144 Walsh
  32. Sumit   Middha
    82 Middha
  33. Jesse   Galle
    16 Galle
  34. Alexander Vincent Penson
    53 Penson
  35. Diana Lauren Mandelker
    153 Mandelker
  36. Christina Tran
    14 Tran
  37. Luis Alberto Diaz
    129 Diaz
  38. Alicia Latham
    50 Latham