Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, and aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF3, FGF4, FGF19/CCND1 amplification, TP53 and CDKN2A alterations, appeared at more advanced stages in aggressive tumors. In 28% of the tumors we identified genetic alterations potentially targetable by 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.

Nuclear bodies (NBs) are ultrastructurally defined granules predominantly found in dividing cells. Here we show that PML, a protein involved in the t(15;17) translocation of acute promyelocytic leukaemia (APL), is specifically bound to a NB. PML and several NB‐associated proteins, found as auto‐antigens in primary biliary cirrhosis (PBC), are co‐localized and co‐regulated. The APL‐derived PML‐RAR alpha fusion protein is shown to be predominantly localized in the cytoplasm, whereas a fraction is nuclear and delocalizes the NB antigens to multiple smaller nuclear clusters devoid of ultrastructural organization. RA administration (which in APL patients induces blast differentiation and consequently complete remissions) causes the re‐aggregation of PML and PBC auto‐antigens onto the NB, while PML‐RAR alpha remains mainly cytoplasmic. Thus, PML‐RAR alpha expression leads to a RA‐reversible alteration of a nuclear domain. These results shed a new light on the pathogenesis of APL and provide a molecular link between NBs and oncogenesis.

Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. However, it is not known how this dual function of Mdm2 on p53 synthesis and degradation is achieved. Here we show that the p53 mRNA region encoding the Mdm2-binding site interacts directly with the RING domain of Mdm2. This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation. We also show that introduction of cancer-derived single silent point-mutations in the p53 mRNA weakens its binding to Mdm2 and results in reduced p53 activity. These data are consistent with a mechanism by which changes in silent nucleotides can affect the function of the encoded protein, and indicate that Mdm2-mediated control of p53 synthesis and degradation has evolved in the p53 mRNA sequence and its encoded amino acids.

Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.

Corresponding author: m.cavazzana@nck.aphp.fr, Professor Marina Cavazzana-Calvo, Biotherapy Department, Hopital Necker EnfantsMalades, 149 rue de Sevres, F-75015 Paris, France; tel. +33 1 44 49 50 68; fax +33 1 44 49 25 05. 18 These authors contributed equally to this work 19 These authors contributed equally to this work Author contributions: C.L.-P. and E.M.S contributed equally to this study by performing most of the experimental work and analysis, with the assistance of C.D.-C. and E.M. C.Picard and F.R.-L. performed apoptotic tests on the fibroblasts, gave critical advices and comments in designing the experiments. Experiments shown in Fig. 4 were performed by V.M. A.D. performed the RNA interference experiments. F.V. provided expertise in histological examination. K.L.S.-S. mapped P6 deletion and found P7 mutation. J.C.M. performed the sequencing project. C.B. performed the genome-wide linkage scan. C.Picard, L.M.N., N.M.W., A.F., M.M.A. and M.C.-C. recruited and diagnosed the RD patients and provide materials for them. F.Calvo gave critical comments in designing the experiments and helped to sequence the healthy and pathological samples. C.Petit contributed to the design of the inner ear experiments, F.Candotti designed and coordinated the sequencing project. C. Picard and L.A. performed the Lodscore analysis. L.A. and A.F. contributed equally to this study. M.C.-C. supervised the overall project. M.C.-C., C.L.-P., E.M.S L.A. and A.F. wrote the paper and added the comments from all authors. Author information: All authors declare that there is no competing financial interests. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Correspondence and requests for materials should be addressed to Marina Cavazzana-Calvo (m.cavazzana@nck.aphp.fr). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 January 1. Published in final edited form as:Nat Genet. We have identified biallelic mutations in the adenylate kinase 2 (AK2) gene in seven patients affected with RD. These mutations resulted in the absence or a strong decrease in protein expression. We then demonstrated that restoration of AK2 expression in the bone marrow cells of RD patients overcomes the neutrophil differentiation arrest underlining its specific requirement in the development of a restricted set of haematopoietic lineages. Lastly, we established that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation to the sensorineural deafness. These results suggest a novel mechanism regulating haematopoetic cell differentiation, and involved in one of the most severe human immunodeficiency syndromes.The term "reticular dysgenesis" (RD), was coined in 1959 by de Vall and Seyneheve 1 and relates to the histological findings in primary and secondary lymphohaematopoietic organs, where the scarcity of cells highlights the prominent reticular tissue framework. The lack of polymorphonuclear neutrophils (PMNs) in affected patien...

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The physiological role of the subtilisin/kexin-like proprotein convertases (PCs) in rodents has been examined through the use of knockout mice. This review will summarize the major in vivo defects that result from the disruption of the expression of their genes. This includes abnormal embryonic development, hormonal disorder, infertility, and/or modified lipid/sterol metabolism. Members of the PC family play a central role in the processing of various protein precursors ranging from hormones and growth factors to bacterial toxins and viral glycoproteins. Proteolysis occurring at basic residues is mediated by the basic amino acid-specific proprotein convertases, namely: PC1/3, PC2, furin, PACE4, PC4, PC5/6, and PC7. In contrast, proteolysis at nonbasic residues is performed by the subtilisin/kexin-like isozyme-1 (SKI-1/S1P) and the newly identified neural apoptosis-regulated convertase-1 (PCSK9/NARC-1). In addition to their requirement for many physiological processes, these enzymes are also involved in various pathologies such as cancer, obesity, diabetes, lipid disorders, infectious diseases, atherosclerosis and neurodegenerative diseases.