Germline multigene panel testing of patients with endometrial cancer

Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10 −17 ] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH ); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE / POLD1 ; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Population‐specific validation and comparison of the performance of 77‐ and 313‐variant polygenic risk scores for breast cancer risk prediction

“…The CZECANCA panel targeted 226 known and candidate cancer predisposition genes and was described in detail previously. [19][20][21] The PRSMAN panel was designed to target 883 PRS-associated variants in breast, ovarian, and other cancer types that were published by July 2020 (Table S1). 8,10,[15][16][17][22][23][24][25][26][27][28][29][30][31][32][33][34][35] The Roche probe design algorithm excluded 39 SNPs from the PRSMAN panel before its production.…”

“…The NGS libraries were prepared with KAPA HyperPlus/EvoPlus Library Preparation Kits (Roche) according to the manufacturer with minor modifications described previously. 19,21,36 The target regions were captured with pooled CZECANCA and PRSMAN panels in a 2:1 ratio. Sequencing was performed with NextSeq 500 instruments (Illumina, San Diego, California).…”