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
    505 Bajorin
  2. Kenneth Offit
    604 Offit
  3. Leonard B Saltz
    665 Saltz
  4. Mark E Robson
    453 Robson
  5. David Solit
    541 Solit
  6. Neil Howard Segal
    139 Segal
  7. Liying Zhang
    107 Zhang
  8. Zsofia Kinga Stadler
    199 Stadler
  9. Diane Lauren Reidy
    197 Reidy
  10. Yelena Yuriy Janjigian
    189 Janjigian
  11. David S Klimstra
    912 Klimstra
  12. Marc Ladanyi
    1041 Ladanyi
  13. Jinru Shia
    529 Shia
  14. Martin R Weiser
    379 Weiser
  15. Rona Denit Yaeger
    118 Yaeger
  16. David Hyman
    301 Hyman
  17. Ahmet Zehir
    212 Zehir
  18. Mark Andrew Dickson
    100 Dickson
  19. Eileen O'Reilly
    422 O'Reilly
  20. Vijai Joseph
    146 Joseph
  21. Michael Forman Berger
    497 Berger
  22. Deborah F DeLair
    98 DeLair
  23. Barry Stephen Taylor
    189 Taylor
  24. Yelena Kemel
    27 Kemel
  25. Karen Anne Cadoo
    65 Cadoo
  26. Maria Isabel Carlo
    46 Carlo
  27. Jose T Baselga
    461 Baselga
  28. Jaclyn Frances Hechtman
    160 Hechtman
  29. Margaret Rebecca Graham Sheehan
    11 Sheehan
  30. Michael Francis Walsh
    73 Walsh
  31. Sumit   Middha
    77 Middha
  32. Jesse   Galle
    5 Galle
  33. Alexander Vincent Penson
    31 Penson
  34. Christina Tran
    10 Tran
  35. Luis Alberto Diaz
    44 Diaz