Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification
Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification
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DOI：
10.1016/j.jhep.2017.05.014
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发表时间：
2017-10-01
影响因子：
25.7
通讯作者：
Zucman-Rossi, Jessica
中科院分区：
文献类型：
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作者：
Calderaro, Julien;Couchy, Gabrielle;Zucman-Rossi, Jessica
背景与目的：我们对肝细胞癌生物学的日益了解为个体化治疗提供了希望，但将其转化为临床实践需要精确了解其与肿瘤表型的关系。方法：我们的目标是研究大量肝细胞癌的分子表型相关性。结果：CTNNB1(40%)和TP53(21%)突变是相互排斥的，并定义了两个具有不同表型特征的主要肝细胞癌群体。CTNNB1突变的肿瘤体积大(p=0.002)，分化好(p<；0.001)，胆汁淤积(p<；0.001)，有小梁型(p<；0.001)和假腺型(p<；0.001)，无炎性浸润物(p<；0.001)。突变型肿瘤分化差(p<；0.001)，形态致密(p=0.02)，多核(p=0.01)，细胞多形(p=0.02)，血管侵犯频繁(p=0.02)。世界卫生组织(WHO)对组织亚型的分类也与分子特征密切相关。硬化型与Tsc1/Tsc2突变(p=0.005)、上皮向间充质转化和祖细胞表达谱相关。脂肪肝亚型IL-6/JAK/STAT激活频繁，无CTNNB1、TERT和TP53通路改变(p=0.01)。病理检查发现了一种新的亚型，命名为“大梁瘤”，与低存活率(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)和成纤维细胞生长因子19扩增(p=0.02)有关，这些特征也在癌症基因组图谱数据中得到了验证。最后，结合肝细胞癌的病理特征和转录水平分类，发现肿瘤亚型与G1-G6亚型密切相关。结论：肝癌表型与基因突变和转录水平密切相关。这些发现可能有助于将我们对肝癌生物学的知识转化为临床实践。总结：无论在病理还是分子水平上，肝癌都是一种非常异质性的肿瘤。我们在这里表明，肝癌的表型与其分子变化和潜在的致癌途径密切相关。(C)2017年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
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.Methods: 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.Results: 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-mas sive" 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.Conclusion: 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.