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
DOI/URL:
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
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MSK Authors
  1. Dean Bajorin
    404 Bajorin
  2. Kenneth Offit
    509 Offit
  3. Leonard B Saltz
    580 Saltz
  4. Mark E Robson
    365 Robson
  5. David Solit
    431 Solit
  6. Neil Howard Segal
    101 Segal
  7. Liying Zhang
    88 Zhang
  8. Zsofia Kinga Stadler
    144 Stadler
  9. Diane Lauren Reidy
    146 Reidy
  10. Yelena Yuriy Janjigian
    145 Janjigian
  11. David S Klimstra
    843 Klimstra
  12. Marc Ladanyi
    863 Ladanyi
  13. Jinru Shia
    450 Shia
  14. Martin R Weiser
    338 Weiser
  15. Rona Denit Yaeger
    64 Yaeger
  16. David Hyman
    181 Hyman
  17. Ahmet Zehir
    149 Zehir
  18. Mark Andrew Dickson
    77 Dickson
  19. Eileen O'Reilly
    316 O'Reilly
  20. Vijai Joseph
    117 Joseph
  21. Michael Forman Berger
    380 Berger
  22. Deborah F DeLair
    86 DeLair
  23. Barry Stephen Taylor
    138 Taylor
  24. Yelena Kemel
    13 Kemel
  25. Karen Anne Cadoo
    27 Cadoo
  26. Maria Isabel Carlo
    22 Carlo
  27. Jose T Baselga
    395 Baselga
  28. Michael Francis Walsh
    46 Walsh
  29. Sumit   Middha
    52 Middha
  30. Jesse   Galle
    5 Galle
  31. Alexander Vincent Penson
    15 Penson
  32. Christina Tran
    4 Tran
  33. Luis Alberto Diaz
    15 Diaz