Cancer susceptibility mutations in patients with urothelial malignancies Journal Article


Authors: Carlo, M. I.; Ravichandran, V.; Srinavasan, P.; Bandlamudi, C.; Kemel, Y.; Ceyhan-Birsoy, O.; Mukherjee, S.; Mandelker, D.; Chaim, J.; Knezevic, A.; Rana, S.; Fnu, Z.; Breen, K.; Arnold, A. G.; Khurram, A.; Tkachuk, K.; Cipolla, C. K.; Regazzi, A.; Hakimi, A. A.; Al-Ahmadie, H.; Dalbagni, G.; Cadoo, K. A.; Walsh, M. F.; Teo, M. Y.; Funt, S. A.; Coleman, J. A.; Bochner, B. H.; Iyer, G.; Solit, D. B.; Stadler, Z. K.; Zhang, L.; Rosenberg, J. E.; Taylor, B. S.; Robson, M. E.; Berger, M. F.; Vijai, J.; Bajorin, D. F.; Offit, K.
Article Title: Cancer susceptibility mutations in patients with urothelial malignancies
Abstract: PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
Journal Title: Journal of Clinical Oncology
Volume: 38
Issue: 5
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2020-02-10
Start Page: 406
End Page: 414
Language: English
DOI: 10.1200/jco.19.01395
PUBMED: 31794323
PROVIDER: scopus
DOI/URL:
Notes: Article -- Author Preethi Srinivasan's last name is misspelled on the original publication -- Authors Fnu Zarina and Vijai Joseph's first and last names are reversed on the original publication -- Export Date: 2 March 2020 -- Source: Scopus
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MSK Authors
  1. Jonathan Coleman
    215 Coleman
  2. Joshua Chaim
    26 Chaim
  3. Dean Bajorin
    504 Bajorin
  4. Kenneth Offit
    596 Offit
  5. Guido Dalbagni
    269 Dalbagni
  6. Mark E Robson
    444 Robson
  7. David Solit
    529 Solit
  8. Liying Zhang
    106 Zhang
  9. Zsofia Kinga Stadler
    192 Stadler
  10. Gopakumar Vasudeva Iyer
    164 Iyer
  11. Bernard Bochner
    354 Bochner
  12. Vijai Joseph
    143 Joseph
  13. Michael Forman Berger
    489 Berger
  14. Barry Stephen Taylor
    181 Taylor
  15. Ashley Regazzi
    46 Regazzi
  16. Angela Arnold
    32 Arnold
  17. Yelena Kemel
    26 Kemel
  18. Jonathan Eric Rosenberg
    292 Rosenberg
  19. Abraham Ari Hakimi
    176 Hakimi
  20. Karen Anne Cadoo
    60 Cadoo
  21. Maria Isabel Carlo
    46 Carlo
  22. Samuel Aaron Funt
    38 Funt
  23. Michael Francis Walsh
    70 Walsh
  24. Min Yuen   Teo
    43 Teo
  25. Ozge Birsoy
    20 Birsoy
  26. Satshil Rana
    9 Rana
  27. Kelsey E Breen
    3 Breen
  28. Fnu Zarina
    1 Zarina