ObjectivesTo comprehensively analyse the global scientific outputs of hepatocellular carcinoma (HCC) research.MethodsData of publications were downloaded from the Web of Science Core Collection. We used CiteSpace IV and Excel 2016 to analyse literature information, including journals, countries/regions, institutes, authors, citation reports and research frontiers.ResultsUntil March 31, 2018, a total of 24,331 papers in HCC research were identified as published between 2008 and 2017. Oncotarget published the most papers. China contributed the most publications and the United States occupied leading positions in H-index value and the number of ESI top papers. Llovet JM owned the highest co-citations. The keyword “transarterial chemoembolization” ranked first in the research front-line.ConclusionsThe amount of papers published in HCC research has kept increasing since 2008. China showed vast progress in HCC research, but the United States was still the dominant country. Transarterial chemoembolization, epithelial-mesenchymal transition, and cancer stem cell were the latest research frontiers and should be paid more attention.

Purpose This study was performed to further our understanding of the biological and genetic basis of follicular lymphoma (FL) and to identify potential novel therapy targets. Experimental Design We analyzed previously generated whole exome sequencing data of 23 FL cases and one transformed FL case and expanded findings to a combined total of 125 FL/ 3 t-FL. We modeled the 3D-location of RRAGC-associated hotspot mutations. We performed functional studies on novel RRAGC mutants in stable retrovirally transduced HEK293T cells, stable lentivirally transduced lymphoma cell lines and in Saccharomyces cerevisiae. Results We report recurrent mutations, including multiple amino acid hotspots, in the small G-protein RRAGC, which is part of a protein complex that signals intracellular amino acid concentrations to MTOR, in 9.4% of FL cases. Mutations in RRAGC distinctly clustered on one protein surface area surrounding the GTP/GDP binding sites. Mutated RRAGC proteins demonstrated increased binding to RPTOR (raptor) and substantially decreased interactions with the product of the tumor suppressor gene FLCN (folliculin). In stable retrovirally transfected 293T cells, cultured in the presence or absence of leucine, multiple RRAGC mutations demonstrated elevated MTOR activation as evidenced by increased RPS6KB/S6-kinase phosphorylation. Similar activation phenotypes were uncovered in yeast engineered to express mutations in the RRAGC homolog Gtr2 and in multiple lymphoma cell lines expressing HA-tagged RRAGC mutant proteins. Conclusions Our discovery of activating mutations in RRAGC in ~10% of FL provides the mechanistic rationale to study mutational MTOR activation and MTOR inhibition as a potential novel actionable therapeutic target in FL.

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