Germline drivers of gynecologic carcinosarcomas Journal Article


Authors: Sia, T. Y.; Gordhandas, S. B.; Birsoy, O.; Kemel, Y.; Maio, A.; Salo-Mullen, E.; Sheehan, M.; Hensley, M. L.; Rubinstein, M.; Makker, V.; Grisham, R. N.; O'Cearbhaill, R. E.; Roche, K. L.; Mueller, J. J.; Leitao, M. M. Jr; Sonoda, Y.; Chi, D. S.; Abu-Rustum, N. R.; Berger, M. F.; Ellenson, L. H.; Latham, A.; Stadler, Z.; Offit, K.; Aghajanian, C.; Weigelt, B.; Mandelker, D.; Liu, Y. L.
Article Title: Germline drivers of gynecologic carcinosarcomas
Abstract: Objectives: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. Methods: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. Results: Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15). Conclusions: gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members. © 2023 Elsevier Inc.
Keywords: human tissue; aged; major clinical study; cancer patient; endometrium carcinoma; homologous recombination; cancer susceptibility; prevalence; cohort analysis; brca1 protein; brca2 protein; carcinogenesis; heterozygosity loss; lynch syndrome; protein msh6; genetic testing; rad51 protein; penetrance; carcinosarcoma; germline mutation; ovarian carcinosarcoma; human; female; article; endometrial carcinosarcoma; dna mismatch repair protein msh2; germline pathogenic variants; gynecologic carcinosarcomas
Journal Title: Gynecologic Oncology
Volume: 174
ISSN: 10956859
Publisher: Elsevier B.V.  
Date Published: 2023-07-01
Start Page: 34
End Page: 41
Language: English
DOI: 10.1016/j.ygyno.2023.04.024
PUBMED: 37149903
PROVIDER: scopus
PMCID: PMC10330315
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Ying L. Liu -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    268 Makker
  2. Kenneth Offit
    792 Offit
  3. Dennis S Chi
    715 Chi
  4. Yukio Sonoda
    476 Sonoda
  5. Mario Leitao
    582 Leitao
  6. Zsofia Kinga Stadler
    397 Stadler
  7. Rachel Nicole Grisham
    175 Grisham
  8. Martee L Hensley
    290 Hensley
  9. Michael Forman Berger
    774 Berger
  10. Yelena Kemel
    107 Kemel
  11. Britta Weigelt
    645 Weigelt
  12. Jennifer Jean Mueller
    187 Mueller
  13. Margaret Rebecca Graham Sheehan
    46 Sheehan
  14. Diana Lauren Mandelker
    185 Mandelker
  15. Ozge Birsoy
    71 Birsoy
  16. Ying Liu
    109 Liu
  17. Alicia Latham
    62 Latham
  18. Lora Hedrick Ellenson
    112 Ellenson
  19. Anna Maio
    36 Maio
  20. Tiffany Yilan Sia
    31 Sia