Comprehensive analysis of germline drivers in endometrial cancer

Autor: Sushmita Gordhandas, Eric Rios-Doria, Karen A Cadoo, Amanda Catchings, Anna Maio, Yelena Kemel, Margaret Sheehan, Megha Ranganathan, Dina Green, Anjali Aryamvally, Angela G Arnold, Erin Salo-Mullen, Beryl Manning-Geist, Tiffany Sia, Pier Selenica, Arnaud Da Cruz Paula, Chad Vanderbilt, Maksym Misyura, Mario M Leitao, Jennifer J Mueller, Vicky Makker, Maria Rubinstein, Claire F Friedman, Qin Zhou, Alexia Iasonos, Alicia Latham, Maria I Carlo, Yonina R Murciano-Goroff, Marie Will, Michael F Walsh, Shirin Issa Bhaloo, Lora H Ellenson, Ozge Ceyhan-Birsoy, Michael F Berger, Mark E Robson, Nadeem Abu-Rustum, Carol Aghajanian, Kenneth Offit, Zsofia Stadler, Britta Weigelt, Diana L Mandelker, Ying L Liu
Rok vydání: 2023
Předmět:
Zdroj: JNCI: Journal of the National Cancer Institute. 115:560-569
ISSN: 1460-2105
0027-8874
DOI: 10.1093/jnci/djad016
Popis: Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.
Databáze: OpenAIRE
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