Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer Journal Article


Authors: Cadoo, K. A.; Mandelker, D. L.; Mukherjee, S.; Stewart, C.; DeLair, D.; Ravichandran, V.; Srinivasan, P.; Hurley, D.; Kemel, Y.; Arnold, A. G.; Sheehan, M.; Pradhan, N.; Joseph, V.; Chi, D. S.; Gardner, G. J.; Jewell, E. L.; Leitao, M. M. Jr; Long Roche, K.; Mueller, J. J.; Sonoda, Y.; Zivanovic, O.; Walsh, M.; Carlo, M. I.; Berger, M. F.; Hyman, D. M.; Zhang, L.; Robson, M. E.; Offit, K.; Aghajanian, C.; Abu-Rustum, N. R.; Stadler, Z.
Article Title: Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer
Abstract: PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board-approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel-the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets-that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability-high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations. (C) 2019 by American Society of Clinical Oncology
Keywords: germline; practice guideline; breast-cancer; women; nonpolyposis colorectal-cancer; lynch-syndrome; american-college; susceptibility gene-mutations; medical-genetics; national-society
Journal Title: JCO Precision Oncology
Volume: 3
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2019-01-01
Language: English
ACCESSION: WOS:000493089500001
DOI: 10.1200/PO.18.00338
PROVIDER: wos
Notes: Source: Wos
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MSK Authors
  1. Ginger J Gardner
    158 Gardner
  2. Elizabeth Jewell
    60 Jewell
  3. Kenneth Offit
    579 Offit
  4. Dennis S Chi
    523 Chi
  5. Mark E Robson
    436 Robson
  6. Yukio Sonoda
    307 Sonoda
  7. Mario Leitao
    342 Leitao
  8. Liying Zhang
    102 Zhang
  9. Oliver Zivanovic
    145 Zivanovic
  10. Zsofia Kinga Stadler
    188 Stadler
  11. David Hyman
    279 Hyman
  12. Kara Christine Long
    78 Long
  13. Vijai Joseph
    136 Joseph
  14. Michael Forman Berger
    481 Berger
  15. Deborah F DeLair
    96 DeLair
  16. Angela Arnold
    31 Arnold
  17. Yelena Kemel
    24 Kemel
  18. Karen Anne Cadoo
    56 Cadoo
  19. Maria Isabel Carlo
    43 Carlo
  20. Jennifer Jean Mueller
    41 Mueller
  21. Margaret Rebecca Graham Sheehan
    11 Sheehan
  22. Michael Francis Walsh
    66 Walsh
  23. Nisha Pradhan
    11 Pradhan