Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B −/−:89A3B +/−:27A3B +/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.

AbsatractAlong with the constant improvement in high-throughput sequencing technology, an increasing number of transcriptome sequencing projects are carried out in organisms without decoded genome information and even on environmental biological samples. To study the biological functions of novel transcripts, the very first task is to identify their potential functions. We present a web-based annotation tool, FunctionAnnotator, which offers comprehensive annotations, including GO term assignment, enzyme annotation, domain/motif identification and predictions for subcellular localization. To accelerate the annotation process, we have optimized the computation processes and used parallel computing for all annotation steps. Moreover, FunctionAnnotator is designed to be versatile, and it generates a variety of useful outputs for facilitating other analyses. Here, we demonstrate how FunctionAnnotator can be helpful in annotating non-model organisms. We further illustrate that FunctionAnnotator can estimate the taxonomic composition of environmental samples and assist in the identification of novel proteins by combining RNA-Seq data with proteomics technology. In summary, FunctionAnnotator can efficiently annotate transcriptomes and greatly benefits studies focusing on non-model organisms or metatranscriptomes. FunctionAnnotator, a comprehensive annotation web-service tool, is freely available online at: http://fa.cgu.edu.tw/. This new web-based annotator will shed light on field studies involving organisms without a reference genome.

BackgroundPatient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets.MethodsWe established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs.ResultsA relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients’ plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer.ConclusionsOur integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0873-5) contains supplementary material, which is available to authorized users.

Background. Osteonecrosis of the femoral head (ONFH) contributes to 45% of total hip replacements (THRs) annually in Taiwan. Nontraumatic ONFH (NONFH) is multifactorial; no effective Western medicine is available to delay the disease process. This population-based cohort study investigated the association of traditional Chinese medicine (TCM) therapy with risk of THR in patients with NONFH. Methods. This retrospective study was conducted using claims data from all insured residents covered by the National Health Insurance from 2000 to 2010. We enrolled 1,680 newly diagnosed ONFH patients who had not undergone THR, before or within 6 months after diagnosis of ONFH; these patients did not exhibit hip fracture or dislocation before the endpoint. In total, 595 propensity score-matched pairs were selected from among 1,028 TCM users and 652 non-TCM users. The association between TCM use and risk of THR was analyzed using a Cox proportional hazard model. Kaplan-Meier and log rank tests were performed to plot the cumulative incidence of THR. Results. The mean follow-up periods were 5.00 years and 3.57 years for TCM and non-TCM cohorts, respectively. Compared to the non-TCM cohort, the TCM cohort had fewer patients undergoing THR surgery (25.4% vs. 18.2%, adjusted hazard ratio: 0.60, p<0.0001). The risk of reduction was noted in the group aged 30–59 years (adjusted hazard ratio: 0.56, p<0.0001), but there was no association with gender nor socioeconomic status. There was a significantly lower cumulative incidence of THR in TCM users (p<0.0001). Shu-Jing-Huo-Xue-Tang and Yan Hu Suo were the most frequently prescribed formula and single herb, respectively. Conclusions. NONFH patients using TCM had a lower risk of THR; the risk of reduction was noted in the group aged 30–59 years but was not associated with gender nor socioeconomic status. TCM might be useful in conservative treatment for NONFH.