子宫内膜癌种系驱动因素的综合分析。
Comprehensive analysis of germline drivers in endometrial cancer.
机构信息
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
St. James's Hospital, Trinity St. James's Cancer Institute, Dublin, Ireland.
出版信息
J Natl Cancer Inst. 2023 May 8;115(5):560-569. doi: 10.1093/jnci/djad016.
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.
背景
我们旨在确定在未经选择的子宫内膜癌（EC）患者中种系致病性变异（gPVs）的流行率，确定肿瘤内的双等位基因 gPVs，并描述它们与临床病理特征的关联。
方法
从 2015 年 1 月 1 日至 2021 年 6 月 30 日，对接受临床肿瘤-正常 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets（MSK-IMPACT）测序的 EC 患者进行了至少 76 种癌症易感性基因的种系评估。在存在 gPVs 的患者中，通过分析杂合性丢失和体细胞 PVs 来确定 EC 中的双等位基因改变。使用非参数检验比较临床病理变量。
结果
在 1625 名 EC 患者中，有 216 名（13%）存在 gPVs，有 15 名患者存在 2 种 gPVs。在 35 个基因中存在 231 个 gPVs（75 个[32%]高外显率；39 个[17%]中度外显率；117 个[51%]低、隐性或不确定外显率）。与没有 gPVs 的患者相比，有 gPVs 的患者更年轻（P = .002），更常为白人（P = .009），肥胖程度较低（P = .025），肿瘤组织学和分子亚型分布存在差异（P = .017）。在 231 个 gPVs 中，74 个（32%）在肿瘤内表现出双等位基因失活。对于高外显率的 gPVs，63%（75 个中的 47 个）的 EC 存在双等位基因改变，主要影响错配修复（MMR）和同源重组相关基因，包括 BRCA1、BRCA2、RAD51D 和 PALB2。双等位基因失活在不同的分子亚型中存在差异，在微卫星不稳定高（MSI-H）或拷贝数（CN）高亚型中发生率最高（POLE 中的 3 个[25%]，MSI-H 中的 30 个[39%]，CN-高的 60 个中的 27 个[45%]，CN-低的 57 个中的 9 个[16%]；P < .001）。
结论
在未经选择的 EC 患者中，有 13%存在 gPVs，其中 63%的高外显率基因（MMR 和同源重组）中的 gPVs 表现出双等位基因失活，可能导致癌症的发生。这支持对 EC 进行种系评估，因为这对治疗和癌症预防有影响。
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