Zhu Chunrong, Zhu Liangjun, Gu Yanhong, Liu Ping, Tong Xiaoling, Wu Guozhong, Zhu Wenyu, Shen Wenxiang, Bao Hua, Ma Xiangyuan, Yu Ruoying, Wu Xue, Zhu Dongqin, Shu Yongqian, Feng Jifeng
The First Affiliated Hospital of Soochow University, Suzhou, China.
Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
Front Genet. 2021 Sep 14;12:608742. doi: 10.3389/fgene.2021.608742. eCollection 2021.
Gastrointestinal tract cancers have high incidence and mortality in China, but their molecular characteristics have not been fully investigated. We sequenced 432 tumor samples from the colorectum, stomach, pancreas, gallbladder, and biliary tract to investigate cancer-related mutations and detail the landscape of microsatellite instability (MSI), tumor mutation burden (TMB), and chromosomal instability (CIN). We observed the highest TMB in colorectal and gastric cancers and the lowest TMB in gastrointestinal stromal tumors (GISTs). Twenty-four hyper-mutated tumors were identified only in colorectal and gastric cancers, with a significant enrichment of mutations in the polymerase genes (, , and ) and mismatch repair (MMR) genes. Additionally, CIN preferentially occurred in colorectal and gastric cancers, while pancreatic, gallbladder, and biliary duct cancers had a much lower CIN. High CIN was correlated with a higher prevalence of malfunctions in chromosome segregation and cell cycle genes, including the copy number loss of , , , and , and the copy number gain of , , , and . In addition, mutations were more abundant in high-CIN tumors, while mutations were more frequent in low-CIN tumors. In colorectal and gastric cancers, tumors with MSI demonstrated much fewer copy number changes than microsatellite stable (MSS) tumors. In colorectal and gastric cancers, the molecular characteristics of tumors revealed the mutational diversity between the different anatomical origins of tumors. This study provides novel insights into the molecular landscape of Chinese gastrointestinal cancers and the genetic differences between tumor locations, which could be useful for future clinical patient stratification and targeted interventions.
在中国，胃肠道癌症的发病率和死亡率都很高，但其分子特征尚未得到充分研究。我们对来自结肠、胃、胰腺、胆囊和胆道的432个肿瘤样本进行了测序，以研究癌症相关突变，并详细分析微卫星不稳定性（MSI）、肿瘤突变负荷（TMB）和染色体不稳定性（CIN）的情况。我们观察到结直肠癌和胃癌中的TMB最高，而胃肠道间质瘤（GIST）中的TMB最低。仅在结直肠癌和胃癌中鉴定出24个高突变肿瘤，其聚合酶基因（ 、 和 ）和错配修复（MMR）基因中的突变显著富集。此外，CIN优先发生在结直肠癌和胃癌中，而胰腺癌、胆囊癌和胆管癌的CIN则低得多。高CIN与染色体分离和细胞周期基因功能障碍的较高发生率相关，包括 、 、 和 的拷贝数丢失，以及 、 、 和 的拷贝数增加。此外， 突变在高CIN肿瘤中更为丰富，而 突变在低CIN肿瘤中更为频繁。在结直肠癌和胃癌中，MSI肿瘤的拷贝数变化比微卫星稳定（MSS）肿瘤少得多。在结直肠癌和胃癌中，肿瘤的分子特征揭示了不同解剖学起源肿瘤之间的突变多样性。本研究为中国胃肠道癌症的分子图谱以及肿瘤部位之间的遗传差异提供了新的见解，这可能有助于未来临床患者分层和靶向干预。
