Targeted and shallow whole genome sequencing identifies therapeutic opportunities in p53abn endometrial cancers

Purpose:
Shallow whole genome sequencing (sWGS) can detect copy number (CN) aberrations. In high-grade serous ovarian (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers (ECs) to identify additional prognostic stratification and therapeutic opportunities.

Experimental Design:
sWGS and targeted panel sequencing was performed on formalin-fixed paraffin-embedded p53abn ECs. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed.

Results:
In 187 p53abn ECs, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. 22% potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with whole genome duplication, and CCNE1, ERBB2 and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. 28% of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. 34% of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on immunohistochemistry, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations.

Conclusions:
sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.EGA study EGAS00001007661

研究目的：浅层全基因组测序（shallow whole genome sequencing, sWGS）可检测拷贝数（copy number, CN）变异。在高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）中，sWGS可识别如同源重组缺陷（homologous recombination deficiency, HRD）这类拷贝数特征以指导临床治疗。本研究将sWGS联合靶向测序应用于p53异常（p53abn）子宫内膜癌（endometrial cancers, ECs），以期识别额外的预后分层指标与治疗靶点。

实验设计：对福尔马林固定石蜡包埋的p53abn子宫内膜癌样本开展sWGS及靶向面板测序。分析获取拷贝数变异、突变数据与拷贝数特征，并评估其与临床病理特征及预后数据的关联。

研究结果：本研究纳入187例p53abn子宫内膜癌患者，共鉴定出5种独特的拷贝数特征。特征5与BRCA1/2拷贝数缺失相关，其特征与HGSOC的HRD特征相似。本研究共检出22%的潜在HRD病例，其中35例为特征5阳性，8例携带BRCA1/2体细胞突变。特征3与特征4与全基因组重复事件相关，且伴随CCNE1、ERBB2及MYC扩增；PIK3CA突变在特征3中富集。我们观察到，特征2阳性患者的总生存期（overall survival, OS）更长，而特征1与特征3阳性患者的总生存期更短。28%的患者存在CCNE1扩增，该亚组多为癌肉瘤组织学类型。所有组织学类型的患者中，34%存在ERBB2扩增及/或免疫组化检测HER2过表达，该表型与不良预后相关。PPP2R1A（29%）与FBXW7（16%）突变位列最常见的5种突变之一。

研究结论：sWGS联合靶向测序可为75%的p53abn子宫内膜癌患者识别治疗机会。未来仍需开展进一步研究，以明确针对上述识别通路的治疗方案在p53abn子宫内膜癌中的疗效。本研究为EGA收录研究项目EGAS00001007661。