Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing Journal Article


Authors: Mandelker, D.; Zhang, L.; Kemel, Y.; Stadler, Z. K.; Joseph, V.; Zehir, A.; Pradhan, N.; Arnold, A.; Walsh, M. F.; Li, Y.; Balakrishnan, A. R.; Syed, A.; Prasad, M.; Nafa, K.; Carlo, M. I.; Cadoo, K. A.; Sheehan, M.; Fleischut, M. H.; Salo-Mullen, E.; Trottier, M.; Lipkin, S. M.; Lincoln, A.; Mukherjee, S.; Ravichandran, V.; Cambria, R.; Galle, J.; Abida, W.; Arcila, M. E.; Benayed, R.; Shah, R.; Yu, K.; Bajorin, D. F.; Coleman, J. A.; Leach, S. D.; Lowery, M. A.; Garcia-Aguilar, J.; Kantoff, P. W.; Sawyers, C. L.; Dickler, M. N.; Saltz, L.; Motzer, R. J.; O'Reilly, E. M.; Scher, H. I.; Baselga, J.; Klimstra, D. S.; Solit, D. B.; Hyman, D. M.; Berger, M. F.; Ladanyi, M.; Robson, M. E.; Offit, K.
Article Title: Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing
Abstract: IMPORTANCE: Guidelines for cancer genetic testing based on family historymay miss clinically actionable genetic changes with established implications for cancer screening or prevention. OBJECTIVE: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. DESIGN, SETTING, AND PARTICIPANTS: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. EXPOSURE: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. MAIN OUTCOMES AND MEASURES: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. RESULTS: Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3%were male, and 81.3%had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95%CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95%CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. CONCLUSIONS AND RELEVANCE: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. © 2017 American Medical Association.
Journal Title: JAMA - Journal of the American Medical Association
Volume: 318
Issue: 9
ISSN: 0098-7484
Publisher: American Medical Association  
Date Published: 2017-09-05
Start Page: 825
End Page: 835
Language: English
DOI: 10.1001/jama.2017.11137
PROVIDER: scopus
PMCID: PMC5611881
PUBMED: 28873162
DOI/URL:
Notes: Maria Arcila's name is misspelled on the original publication -- Article -- Export Date: 2 October 2017 -- Source: Scopus
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MSK Authors
  1. Jonathan Coleman
    184 Coleman
  2. Charles L Sawyers
    153 Sawyers
  3. Dean Bajorin
    404 Bajorin
  4. Kenneth Offit
    509 Offit
  5. Robert Motzer
    744 Motzer
  6. Leonard B Saltz
    580 Saltz
  7. Khedoudja Nafa
    181 Nafa
  8. Mark E Robson
    365 Robson
  9. David Solit
    431 Solit
  10. Maura N Dickler
    237 Dickler
  11. Liying Zhang
    88 Zhang
  12. Zsofia Kinga Stadler
    144 Stadler
  13. David S Klimstra
    843 Klimstra
  14. Marc Ladanyi
    863 Ladanyi
  15. Maeve Aine Lowery
    96 Lowery
  16. Kenneth Ho-Ming Yu
    58 Yu
  17. David Hyman
    181 Hyman
  18. Ahmet Zehir
    149 Zehir
  19. Eileen O'Reilly
    316 O'Reilly
  20. Vijai Joseph
    117 Joseph
  21. Michael Forman Berger
    380 Berger
  22. Maria Eugenia Arcila
    336 Arcila
  23. Howard Scher
    817 Scher
  24. Wassim Abida
    36 Abida
  25. Angela Arnold
    24 Arnold
  26. Yelena Kemel
    13 Kemel
  27. Karen Anne Cadoo
    27 Cadoo
  28. Maria Isabel Carlo
    22 Carlo
  29. Ronak Hasmukh Shah
    43 Shah
  30. Jose T Baselga
    395 Baselga
  31. Aijazuddin Syed
    20 Syed
  32. Rym Benayed
    68 Benayed
  33. Steven Leach
    25 Leach
  34. Meera   Prasad
    11 Prasad
  35. Anne Gunning Lincoln
    14 Lincoln
  36. Michael Francis Walsh
    46 Walsh
  37. Jesse   Galle
    5 Galle
  38. Philip Wayne Kantoff
    62 Kantoff
  39. Yirong Li
    5 Li