Imamura Taisuke, Okamura Yukiyasu, Ohshima Keiichi, Uesaka Katsuhiko, Sugiura Teiichi, Yamamoto Yusuke, Ashida Ryo, Ohgi Katsuhisa, Nagashima Takeshi, Yamaguchi Ken
Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan.
J Hepatobiliary Pancreat Sci. 2023 Mar;30(3):269-282. doi: 10.1002/jhbp.1223. Epub 2022 Aug 31.
Primary liver cancer (PLC) is classified into hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular and intrahepatic cholangiocarcinoma (CHC). We investigated the genomic landscape of PLC according to the histological classification and established a cross-histological molecular subtyping for PLC by a multi-omics analysis.
We analyzed 265 PLC cases with whole-exome sequencing and DNA copy number analyses and 251 cases with gene expression profiling.
The cohort included HCC (n = 223, 84%), ICC (n = 34, 13%), and CHC (n = 8, 3%). Mutation analyses identified histological type-specific driver genes, such as CTNNB1 in HCC and KRAS, IDH1, and PIK3CA in ICC, and ARID1A and KMT2C in CHC. The tumor suppressor gene TP53 mutation was detected in 21.1% of HCC, 16.1% of ICC, and 25.0% of CHC cases. Other well-characterized tumor suppressor genes included RB1, which was mutated in 2.8% of HCC and 3.2% of ICC; and PTEN, which was mutated in 1.4% of HCC, 3.2% of ICC, and 12.5% of CHC cases. DNA copy number analyses identified focal amplifications, with NUF2 (1q23.3) the most frequently detected as an amplified gene in all 3 types (HCC, 3.8%; CHC, 12.5%, ICC, 3.2%). Molecular subtyping for PLC based on the multi-omics analysis identified three subtypes, one of which was associated with recurrence after resection and amplified genes located at chromosome 8q.
Our dataset serves as a fundamental resource for genomic medicine for PLC in Japan and identified amplified genes located at chromosome 8q as promising therapeutic targets for the subgroup with a poor prognosis.
原发性肝癌（PLC）分为肝细胞癌（HCC）、肝内胆管癌（ICC）和肝细胞-肝内胆管癌（CHC）。我们根据组织学分类研究了PLC的基因组格局，并通过多组学分析建立了PLC的跨组织学分子亚型。
我们对265例PLC病例进行了全外显子测序和DNA拷贝数分析，并对251例病例进行了基因表达谱分析。
该队列包括HCC（n = 223，84%）、ICC（n = 34，13%）和CHC（n = 8，3%）。突变分析确定了组织学类型特异性驱动基因，如HCC中的CTNNB1、ICC中的KRAS、IDH1和PIK3CA以及CHC中的ARID1A和KMT2C。肿瘤抑制基因TP53突变在21.1%的HCC、16.1%的ICC和25.0%的CHC病例中被检测到。其他特征明确的肿瘤抑制基因包括RB1，在2.8%的HCC和3.2%的ICC中发生突变；以及PTEN，在1.4%的HCC、3.2%的ICC和12.5%的CHC病例中发生突变。DNA拷贝数分析确定了局部扩增，其中NUF2（1q23.3）是所有三种类型（HCC，3.8%；CHC，12.5%，ICC，3.2%）中最常检测到的扩增基因。基于多组学分析的PLC分子亚型确定了三种亚型，其中一种与切除术后复发以及位于8号染色体q区的扩增基因相关。
我们的数据集是日本PLC基因组医学的基础资源，并确定位于8号染色体q区的扩增基因是预后不良亚组有前景的治疗靶点。
