Moeini A, Sia D, Zhang Z, Camprecios G, Stueck A, Dong H, Montal R, Torrens L, Martinez-Quetglas I, Isabel Fiel M, Hao K, Villanueva A, Thung S, Schwartz M, Llovet J
BACKGROUND AND AIMS Mixed hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy.
METHODS We performed gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA encompassing the whole histological spectrum of the disease. Comparative genomic analysis was performed with independent datasets of HCC (n=164) and iCCA (n=149).
RESULTS Integrative genomic analysis of HCC-CCAs revealed that cholangiolocellular carcinoma (CLC) represents a distinct biliary-derived entity compared with the stem-cell and classical types. CLC tumors were NCAM positive (6/6 vs 1/12, P<0.001), chromosomally stable (mean chromosomal aberrations 5.7 vs 14.1, P=0.008), showed significant upregulation of TGF-beta signaling and enrichment for inflammation-related and immune response signatures (P<0.001). Stem-cell tumors were characterized by SALL4 positivity (6/8 vs 0/10, P<0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e. MYC and IGF), and signatures related to poor clinical outcome. Regarding classical type, a significant correlation in the copy number aberrations of the iCCA and HCC components suggested a clonal origin. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor (mean driver mutations:2). Among those, TP53 was the most frequently mutated gene (6/21, 29%) in HCC-CCAs.
CONCLUSIONS Mixed HCC-CCA represents a heterogeneous group of tumors, with stem-cell type characterized by features of poor prognosis and classical type with common lineage for HCC and iCCA components. CLC stands alone as a distinct biliary-derived entity associated with chromosomal stability and TGF-beta signaling.
LAY SUMMARY The molecular characterization of mixed hepatocellular cholangiocarcinoma (HCC-CCA) defined that cholangiolocellular carcinoma (CLC) is a distinct molecular entity with biliary-derived origin and no traits of HCC. On the other hand, within the mixed HCC-CCA, the stem-cell type shared aggressive phenotype and poor outcome whereas the classic type shows a common cell lineage for both the HCC and the iCCA component. These data supports re-defining the pathological classification of mixed HCC-CCA in light of the novel molecular data provided.
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