Comprehensive analysis of germline drivers in endometrial cancer

Abstract

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 < .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.

Figure 1.

Patient selection. The figure depicts selection of final cohort of 1625 patients with endometrial cancer (EC) who underwent clinical tumor-normal sequencing with germline assessment of at least 76 genes who were analyzed in this study.

Figure 2.

Germline pathogenic variants and loss of heterozygosity by gene penetrance. The figure depicts the 231 germline pathogenic variants in at least 76 genes, monoallelic vs biallelic, grouped by gene penetrance (high, moderate, low, recessive, and uncertain). Higher levels of biallelic loss were observed in high- and moderate-penetrance genes compared with low-, recessive-, and uncertain-penetrance genes.

Figure 3.

Germline pathogenic variants and loss of heterozygosity by molecular subtype. The figure depicts 231 germline pathogenic variants in at least 76 genes, monoallelic vs biallelic, grouped by molecular subtype. Higher levels of biallelic loss were observed in MSI-H and CN-H tumors compared with CN-L and POLE tumors. CN-H = copy number high; CN-L = copy number low; MSI = microsatellite instability; POLE = polymerase epsilon.

Figure 4.

Clinical characteristics and family histories of patients with germline pathogenic variants (gPVs) in homologous recombination genes RAD51D and PALB2 with biallelic inactivation in tumors. The arrow points to the proband, and “+” indicates presence of pathogenic variant. The figure depicts pedigrees of patients with endometrial cancer (EC) and gPVs in homologous recombination genes RAD51D and PALB2 with biallelic inactivation in tumors. Case 1) Because of a family history of ovarian cancer, the proband underwent risk-reducing bilateral salpingo-oophorectomy (RRSO) without hysterectomy at age 51 years. Subsequently, her sister was diagnosed with triple-negative breast cancer at age 49 years, and multigene panel germline testing identified a RAD51D gPV, which the proband was also found to carry. At age 69 years, the proband was diagnosed with stage IIIC serous EC with biallelic loss of RAD51D. Case 2) The proband was diagnosed with stage IVA EC (mesonephric type) at age 56 years. There was a case of stomach cancer in a maternal grandmother. Case 3) The proband presented with abnormal uterine bleeding at age 49 years and was found to have grade 1 endometrioid adenocarcinoma on endometrial curettage. She underwent total laparoscopic hysterectomy, RRSO, and sentinel lymph node biopsy at age 50 years and was diagnosed with a stage II, grade 1 endometroid EC. Memorial Sloan Kettering Cancer Center–Integrated Mutation Profiling of Actionable Cancer Target sequencing discovered a PALB2 gPV with biallelic loss within the tumor. The proband’s sister, who had a history of estrogen- and progestin receptor–positive breast cancer at age 50 years, underwent cascade testing and was found to share the same PALB2 gPV. Following discovery of the PALB2 gPV, she underwent risk-reducing total laparoscopic hysterectomy and RRSO at age 58 years and had complex atypical hyperplasia bordering on well-differentiated endometrioid EC. Case 4) The proband was diagnosed with stage IA EC at age 62 years with no family history of gynecologic cancers. The proband’s 62-year-old sister also carried the PALB2 gPV and was cancer unaffected.