Germline multigene panel testing of patients with endometrial cancer
Jan Král, Sandra Jelínková, Petra Zemánková, Michal Vočka, Marianna Borecká, Leona Cerna, Marta Černá, Lukáš Dostálek, Petra Duskova, Lenka Foretová, Ondřej Havránek, Klára Horáčková, Milena Hovhannisyan, Štěpán Chvojka, Marta Kalousová, Marcela Kosařová, Monika Koudová, Vera Krutilkova, Eva Macháčková, Petr Nehasil, Jan Novotný, Barbora Otahalova, Alena Puchmajerová, Markéta Šafaříková, J Sláma, Viktor Stránecký, Ivan Šubrt, Spiros Tavandzis, Michal Zikán, Tomáš Zima, Jana Soukupová, Petra Kleiblová, Zdeněk Kleibl, Markéta Janatová
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=1.8x10<sup>‑17</sup>] than the most frequently altered HBOC genes <em>BRCA1</em> (OR, 3.9; 95% CI, 1.6‑9.5; P=0.001), <em>BRCA2</em> (OR, 7.4; 95% CI, 1.9‑28.9; P=0.002) and <em>CHEK2</em> (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 <em>FANCA</em> and <em>MUTYH</em>); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss‑of‑function variants in <em>POLE</em>/<em>POLD1</em>; 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.