Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France; Assistance Publique-Hôpitaux de Paris, Department of Pathology, CHU Henri Mondor, Créteil, France; Université Paris Est Créteil, Faculté de Médecine, Créteil, France.
Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France.
J Hepatol. 2017 Oct;67(4):727-738. doi: 10.1016/j.jhep.2017.05.014. Epub 2017 May 19.
BACKGROUND & AIMS: Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype.
We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC samples were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing.
CTNNB1 (40%) and TP53 (21%) mutations were mutually exclusive and defined two major groups of HCC characterized by distinct phenotypes. CTNNB1 mutated tumours were large (p=0.002), well-differentiated (p<0.001), cholestatic (p<0.001), with microtrabecular (p<0.001) and pseudoglandular (p<0.001) patterns and without inflammatory infiltrates (p<0.001). TP53 mutated tumours were poorly differentiated (p<0.001) with a compact pattern (p=0.02), multinucleated (p=0.01) and pleomorphic (p=0.02) cells and frequent vascular invasion (p=0.02). World Health Organization (WHO) classification of histological subtypes were also strongly related to molecular features. The scirrhous subtype was associated with TSC1/TSC2 mutations (p=0.005), epithelial-to-mesenchymal transition and a progenitor expression profile. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations (p=0.01). Pathological review identified a novel subtype, designated as "macrotrabecular-massive" associated with poor survival (p<0.001), high alpha-fetoprotein serum level (p=0.02), vascular invasion (p<0.001), TP53 mutations (p<0.001) and FGF19 amplifications (p=0.02), features also validated in The Cancer Genome Atlas (TCGA) data. Finally, integration of HCC pathological characteristics with its transcriptomic classification showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups.
HCC phenotypes are tightly associated with gene mutations and transcriptomic classification. These findings may help in translating our knowledge of HCC biology into clinical practice. Lay summary: HCC is a very heterogenous tumour, both at the pathological and molecular levels. We show here that HCC phenotype is tightly associated to its molecular alterations and underlying oncogenic pathways.
我们对肝细胞癌（HCC）生物学的认识不断加深，这为实现个体化治疗带来了希望，然而，要将其转化为临床实践，就需要精确了解其与肿瘤表型的关系。
我们旨在对大量 HCC 样本进行分子表型相关性研究。为此，我们通过病理复查、免疫组织化学、基因表达谱和测序等方法对 343 例手术切除的 HCC 样本进行了研究。
CTNNB1（40%）和 TP53（21%）突变相互排斥，定义了两个主要的 HCC 群体，具有不同的表型特征。CTNNB1 突变型肿瘤较大（p=0.002）、分化较好（p<0.001）、具有胆淤积特征（p<0.001）、具有微小梁（p<0.001）和假腺泡（p<0.001）模式，且无炎症浸润（p<0.001）。TP53 突变型肿瘤分化较差（p<0.001），具有致密模式（p=0.02）、多核（p=0.01）和多形性（p=0.02）细胞，且常伴有血管侵犯（p=0.02）。世界卫生组织（WHO）的组织学亚型分类也与分子特征密切相关。硬纤维瘤亚型与 TSC1/TSC2 突变（p=0.005）、上皮-间充质转化和祖细胞表达谱相关。脂肪性肝炎型表现为频繁的 IL-6/JAK/STAT 激活，而无 CTNNB1、TERT 和 TP53 通路改变（p=0.01）。病理复查确定了一种新的亚型，称为“大小梁-巨块”型，与不良预后（p<0.001）、高甲胎蛋白血清水平（p=0.02）、血管侵犯（p<0.001）、TP53 突变（p<0.001）和 FGF19 扩增（p=0.02）相关，这些特征也在癌症基因组图谱（TCGA）数据中得到了验证。最后，将 HCC 病理特征与转录组分类相结合，显示出表型明显不同的肿瘤亚群，与 G1-G6 亚组密切相关。
HCC 的表型与基因突变和转录组分类密切相关。这些发现可能有助于将我们对 HCC 生物学的认识转化为临床实践。
