BackgroundTo better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.MethodsWe performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.ResultsMutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs.ConclusionOur results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.

Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity.Cisplatin [cis-diamminedichloroplatinum(II)] is an effective antineoplastic agent that was widely applied in the treatment of various types of solid tumors in the past several decades 1-3 . However, due to poor selectivity, cisplatin could cause neurotoxicity, nephrotoxicity, nausea and vomiting, and ototoxicity et al. in clinical [4][5][6][7][8][9][10] . As the principal excretory organ for cisplatin, kidney accumulates and retains platinum to a greater degree than other organs 11,12 . Therefore, nephrotoxicity has long been the most severe and life-threatening toxicity among these side-effects 13,14 . Statistics showed there were about 25-35% patients experienced a significant decline in renal function after receiving a single dose of cisplatin 13,15 . The declines manifested clinically as lower glomerular filtration rate, reduced serum magnesium and potassium levels et al. 13,16 . Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al. [17][18][19][20][21][22] . However, how the toxicity occurs and develops, and how various types of mechanisms are integrated to induce distinct kidney pathology, remain largely unknown.Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions 23,24 . At present, metabolomics analysis encompasses different strategies depending on the objective of study, namely target analysis of a group of c...

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Liver cancer is one of the most common cancers worldwide. CDR3 sequencing-based immune repertoire can be closely associated with cancer prognosis and development. Identifying the specific interaction between the TCR and cellular antigens is important for developing novel immunotherapeutic approaches for the treatment of cancer. The rearranged TCRβ loci amplified using Vβ- and Jβ-specific primers by multi-PCR and sequenced using high-throughput sequencing (HTS) in liver cancers were compared with those of T cells from healthy adult peripheral blood and from adjacent liver tissue. The T-cell repertoires within each tumor show strong similarity to one another but are distinct from those of the circulating T-cell repertoire. In addition, our results demonstrate that there are significant differences in the T-cell repertoires of HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma), and MHC (mixed hepatocellular and cholangiocellular carcinoma). Furthermore, we found that the highly expanded clone (HEC) ratio in blood samples from liver cancer patients differed significantly from those in the blood of healthy adults and hepatitis patients ( < 0.001). The above results suggest that comparison of the T-cell repertoires of tissue and blood could be used to distinguish liver cancer patients from healthy adults and from hepatitis patients. In the future, the diversity of CDR3 sequences in liver cancer may prove to be a useful and novel biomarker for detecting aggressive tumors with high invasive or metastatic capacity.

The identification of potential oncogenes plays an important role in finding novel therapeutic targets for many cancers, including hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. In our previous research, using microarray technology, we found that FAM83D was overexpressed in HCCs. However, whether the overexpression of FAM83D contributes to hepatocarcinogenesis remains unclear. In this study, we found that FAM83D was significantly upregulated in 76.6% (167 of 218) of the HCC specimens at the mRNA level and in 69.44% (50 of 72) of the HCC specimens at the protein level compared with adjacent non-cancerous liver specimens, as indicated by RT-PCR and immunohistochemical staining, respectively. The FAM83DmRNA expression level was positively correlated with the level of alpha-fetoprotein (AFP) (≥100 ng/ml), the clinical TNM stage, the presence of a portal vein tumor thrombus (PVTT), disease-free survival (DFS) and the overall survival (OS) time of the HCC patients (P < 0.05). Knocking down FAM83D significantly promoted the growth of Huh7 and HepG2 cells, as demonstrated in an RNA interference assay. Moreover, the DNA methylation status of the FAM83D promoter was significantly reduced in the HCC specimens with overexpression of FAM83D gene. Our data suggest that the upregulation of FAM83D, a potential oncotarget gene, may be triggered by epigenetic events and can contribute to hepatocarcinogenesis.