Comprehensive analysis of germline drivers in endometrial cancer.
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Gordhandas Sushmita, Rios-Doria Eric, Cadoo Karen A, Catchings Amanda, Maio Anna, Kemel Yelena, Sheehan Margaret, Ranganathan Megha, Green Dina, Aryamvally Anjali, Arnold Angela G, Salo-Mullen Erin, Manning-Geist Beryl, Sia Tiffany, Selenica Pier, Da Cruz Paula Arnaud, Vanderbilt Chad, Misyura Maksym, Leitao Mario M, Mueller Jennifer J, Makker Vicky, Rubinstein Maria, Friedman Claire F, Zhou Qin, Iasonos Alexia, Latham Alicia, Carlo Maria I, Murciano-Goroff Yonina R, Will Marie, Walsh Michael F, Issa Bhaloo Shirin, Ellenson Lora H, Ceyhan-Birsoy Ozge, Berger Michael F, Robson Mark E, Abu-Rustum Nadeem, Aghajanian Carol, Offit Kenneth, Stadler Zsofia, Weigelt Britta, Mandelker Diana L, Liu Ying L
Аннотация
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 < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001).
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.