Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tumors. Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. In conclusion, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.

Somatic mutations activating telomerase reverse-trancriptase promoter were recently identified in several tumour types. Here we identify frequent similar mutations in human hepatocellular carcinomas (59%), cirrhotic preneoplastic macronodules (25%) and hepatocellular adenomas with malignant transformation in hepatocellular carcinomas (44%). In hepatocellular tumours, telomerase reverse-transcripase- and CTNNB1-activating mutations are significantly associated. Moreover, preliminary data suggest that telomerase reverse-trancriptase promoter mutations can increase the expression of telomerase transcript. In conclusion, telomerase reverse-trancriptase promoter mutation is the earliest recurrent genetic event identified in cirrhotic preneoplastic lesions so far and is also the most frequent genetic alteration in hepatocellular carcinomas, arising from both the cirrhotic or non-cirrhotic liver.

To retrospectively evaluate a respiratory-triggered diffusion-weighted (DW) magnetic resonance (MR) imaging sequence combined with parallel acquisition to allow the calculation of pure molecular-based (D) and perfusion-related (D*, f) diffusion parameters, on the basis of the intravoxel incoherent motion (IVIM) theory, to determine if these parameters differ between patients with cirrhosis and patients without liver fibrosis. The institutional review board approved this retrospective study; informed consent was waived. IVIM DW imaging was tested on three alkane phantoms, on which the signal-intensity decay curves according to b factors were logarithmically plotted. Ten b factors (0, 10, 20, 30, 50, 80, 100, 200, 400, 800 sec/mm(2)) were used in patients. Patients with documented liver cirrhosis (cirrhotic liver group, n = 12) and patients without chronic liver disease (healthy liver group, n = 25) were included. The mean liver D, D*, and f values were measured and compared with the apparent diffusion coefficient (ADC) computed by using four b values (0, 200, 400, 800 sec/mm(2)). Liver ADC and D, f, and D* parameters were compared between the cirrhotic liver group and healthy liver group. Means were compared by using the Student t test. Signal-intensity decay curves were monoexponential on phantoms and biexponential in patients. In vivo, mean ADC values were significantly higher than D in the healthy liver group (ADC = 1.39 x 10(-3) mm(2)/sec +/- 0.2 [standard deviation] vs D = 1.10 x 10(-3) mm(2)/sec +/- 0.7) and in the cirrhotic liver group (ADC = 1.23 x 10(-3) mm(2)/sec +/- 0.4 vs D = 1.19 x 10(-3) mm(2)/sec +/- 0.5) (P = .03). ADC and D* were significantly reduced in the cirrhotic liver group compared with those in the healthy liver group (respective P values of .03 and .008). Restricted diffusion observed in patients with cirrhosis may be related to D* variations, which reflect decreased perfusion, as well as alterations in pure molecular water diffusion in cirrhotic livers.