Comprehensive Analysis of Germline Drivers in Endometrial Cancer
Menée à partir de données clinico-pathologiques et de données moléculaires portant sur 1 625 patientes atteintes d'un cancer de l'endomètre, cette étude détermine la prévalence de variants constitutionnels pathogènes au niveau de 76 gènes de prédisposition au cancer puis examine la pénétrance de ces variants ainsi que la présence intratumorale d'inactivations bialléliques
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 ≥ 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT sequencing from 1/1/15-6/30/21. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using non-parametric 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/uncertain-penetrance). Compared to those without gPVs, patients with gPVs were younger (P=.002), more often White (P=.009), 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% (47/75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination (HR) genes, including BRCA1/2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes [3/12 (25%) POLE, 30/77 (39%) MSI-H, 27/60 (45%) CN-H, 9/57 (16%) CN-L, P<.001].
Conclusions : Thirteen percent of unselected patients with EC had gPVs, with 63% of gPVs in high-penetrance genes (MMR and HR) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.
Journal of the National Cancer Institute , article en libre accès, 2022