Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores – mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.

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The presence of sudden-onset abdominal pain is the only independent indicator of ruptured HCC. Hepatic resection, when feasible, is the treatment of choice and can result in an overall survival rate comparable to that of patients with non-ruptured HCC.

Frequent intrahepatic metastasis causes early tumor recurrence and dismaying prognosis of human hepatocellular carcinoma (HCC). We recently identified overexpression of stathmin1 (STMN1) in human HCC. This study was designed to elucidate the clinical and biological significance of overexpression of STMN1 in HCC. Expression of STMN1 was conducted by quantitative reverse transcription-polymerase chain reaction and immunoblotting assays on 58 pairs of HCC and para-tumor liver tissues from patients with HCC along with normal liver tissues as the controls. Association of STMN1 overexpression with tumor recurrence and prognosis was investigated by Kaplan-Meier cumulative survival and Cox Regression analyses. Roles of STMN1 in cell cycle, cell motility, and invasion were determined by in vitro assays. STMN1 overexpression in hepatoma was strongly associated with local invasion (P = 0.031), early recurrence (P = 0.002), and poor prognosis (P = 0.005), and was an independent indicator for tumor recurrence (P = 0.0045). STMN1 overexpression further identified subgroups of HCC patients with higher tumor recurrence and worse prognosis among HCC patients with early tumor stage (T1) or intermediate histological grades (G2 and G3), both of whom represent the majority of HCC patients receiving primary curative hepatectomy. Silencing STMN1 expression via RNA interference suppressed invasion activity, while ectopic expression of STMN1 enhanced cell invasion and caused polyploidy of cells. In conclusion, STMN1 overexpression could predict early tumor recurrence and poor prognosis, particularly at early stage of hepatoma. Overexpression of STMN1 promoted polyploidy formation, tumor-cell invasion, and intrahepatic metastasis, suggesting that STMN1 can be a target for anti-cancer therapy of human hepatoma.

ALP among liver function tests, in addition to other tumor characters were independent factors for DFS and OS; our results suggest that preoperative ALP levels could be utilized to monitor and predict recurrence in high risk HCC patients.

SR can provide survival benefits for patients with 1 or 2 isolated extrahepatic metastases and who concurrently exhibit good hepatic functional reserve and general performance status as well as successful treatment of intrahepatic HCC.

The AA right hepatectomy with liver hanging manoeuvre for large HCC is associated with reduced blood transfusion requirement and lower recurrence rates in the short term.

4. Laryngoscope, 127:2194-2200, 2017.