Chen Chao, Wang Jian, Sun Binjie, Zheng Yuyan, Ge Xiaoxu, Gong Zhiyuan, Gu Haochen, Zhang Zhiwei, Zhu Akao, Shao Yingkuan, Hu Yeting, Ma Lijia, Li Yini, Ding Kefeng, Wang Da, Sun Lifeng
Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Front Immunol. 2025 Jun 11;16:1593439. doi: 10.3389/fimmu.2025.1593439. eCollection 2025.
The ovarian metastases originating from colorectal cancer (CRCOM) develops rapidly and lethally. Previously, the genetic alterations and metastatic pathway in CRCOM were not well understood. The aim of this study is to explore the special molecular phenotype and dissemination patterns of CRCOM.
The whole-exome sequencing (WES) was performed on 65 matched tissue samples from 11 CRCOM patients, including 11 primary colorectal cancer (CRC) with 11 matched normal tissues, and 43 multi-site metastases (including 15 CRCOMs and 4 patients had bilateral ovarian metastases (OMs). Genetic landscape, neoantigens, tumor clonal origin and spread of CRCOMs were analyzed. TCGA-COAD dataset combined with our data were used for survival analysis and validation of the findings.
There was significant intertumoral heterogeneity among patients with CRCOM and intra-tumoral heterogeneity among multiorgan metastases. 19 genes were inferred as the potential driver genes of CRCOM. USP7 and RPA1 were HRD-related mutations and potential to serve as predictive biomarkers in OM. The putative neoantigen number of the primary CRC and OM varies widely among patients. The OM showed an immune desert state, extremely deficient in each subtype of immune cells. According to COSMIC signatures features, the CRCOM patients were divided into two groups, which are different in overall survival (OS) (median OS, 720 days vs 360 days, 0.074) and genetic alterations. Two metastatic patterns of CRCOM were summarized, which were primary CRC to OM, and metastases to metastases (including lymph node metastases (LNM) to OM, peritoneal metastases (PM) to OM, and other metastases to OM). Interestingly, the sources of bilateral OM might be different in the two patients.
This study presents a better understanding the heterogeneity of the genetic characterizations and metastatic pattern in CRCOM. The subtypes of CRCOM with USP7 mutation, more copy number alterations, lower neoantigens, and immunoscore have a worse prognosis.
结直肠癌卵巢转移（CRCOM）进展迅速且预后不良。此前，CRCOM的基因改变和转移途径尚不清楚。本研究旨在探索CRCOM的特殊分子表型和播散模式。
对11例CRCOM患者的65对匹配组织样本进行全外显子测序（WES），包括11例原发性结直肠癌（CRC）及11对匹配的正常组织，以及43个多部位转移灶（包括15个CRCOM，4例患者有双侧卵巢转移（OM））。分析CRCOM的基因图谱、新抗原、肿瘤克隆起源及播散情况。利用TCGA-COAD数据集结合我们的数据进行生存分析及研究结果验证。
CRCOM患者间存在显著的肿瘤间异质性，多器官转移灶存在肿瘤内异质性。推断出19个基因可能是CRCOM的潜在驱动基因。USP7和RPA1是与同源重组缺陷（HRD）相关的突变，有可能作为OM的预测生物标志物。原发性CRC和OM的推定新抗原数量在患者间差异很大。OM呈现免疫荒漠状态，各亚型免疫细胞极度缺乏。根据COSMIC特征，CRCOM患者分为两组，总生存期（OS）（中位OS，720天对360天，P = 0.074）及基因改变不同。总结了CRCOM的两种转移模式，即原发性CRC至OM，以及转移灶至转移灶（包括淋巴结转移（LNM）至OM、腹膜转移（PM）至OM及其他转移至OM）。有趣的是，两名患者双侧OM的来源可能不同。
本研究对CRCOM的基因特征和转移模式的异质性有了更好的理解。具有USP7突变、更多拷贝数改变、更低新抗原及免疫评分的CRCOM亚型预后更差。
