Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma Journal Article

Authors: Carlo, M. I.; Mukherjee, S.; Mandelker, D.; Vijai, J.; Kemel, Y.; Zhang, L.; Knezevic, A.; Patil, S.; Ceyhan-Birsoy, O.; Huang, K. C.; Redzematovic, A.; Coskey, D. T.; Stewart, C.; Pradhan, N.; Arnold, A. G.; Hakimi, A. A.; Chen, Y. B.; Coleman, J. A.; Hyman, D. M.; Ladanyi, M.; Cadoo, K. A.; Walsh, M. F.; Stadler, Z. K.; Lee, C. H.; Feldman, D. R.; Voss, M. H.; Robson, M.; Motzer, R. J.; Offit, K.
Article Title: Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma
Abstract: IMPORTANCE Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. OBJECTIVES To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. DESIGN, SETTING, AND PARTICIPANTS In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. MAIN OUTCOMES AND MEASURES Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. RESULTS Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P =.003). Patients with non-clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P =.001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. CONCLUSIONS AND RELEVANCE Of patients with non-clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.
Keywords: genetics; risk; genomics; kidney cancer; surveillance; breast-cancer; medical; hereditary leiomyomatosis; predisposition; american-college; metastatic cancer
Journal Title: JAMA Oncology
Volume: 4
Issue: 9
ISSN: 2374-2437
Publisher: American Medical Association  
Date Published: 2018-09-01
Start Page: 1228
End Page: 1235
Language: English
ACCESSION: WOS:000444765300016
DOI: 10.1001/jamaoncol.2018.1986
PUBMED: 29978187
PMCID: PMC6584283
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Jonathan Coleman
    220 Coleman
  2. Sujata Patil
    441 Patil
  3. Kenneth Offit
    604 Offit
  4. Robert Motzer
    909 Motzer
  5. Mark E Robson
    453 Robson
  6. Liying Zhang
    107 Zhang
  7. Darren Richard Feldman
    217 Feldman
  8. Zsofia Kinga Stadler
    199 Stadler
  9. Marc Ladanyi
    1041 Ladanyi
  10. Martin Henner Voss
    163 Voss
  11. Yingbei Chen
    276 Chen
  12. David Hyman
    301 Hyman
  13. Vijai Joseph
    146 Joseph
  14. Angela Arnold
    32 Arnold
  15. Yelena Kemel
    27 Kemel
  16. Abraham Ari Hakimi
    181 Hakimi
  17. Karen Anne Cadoo
    65 Cadoo
  18. Maria Isabel Carlo
    46 Carlo
  19. Chung-Han   Lee
    60 Lee
  20. Devyn Taylor Coskey
    13 Coskey
  21. Michael Francis Walsh
    73 Walsh
  22. Kuo-Cheng Huang
    5 Huang
  23. Nisha Pradhan
    11 Pradhan
  24. Ozge Birsoy
    20 Birsoy