The integrated discrimination improvement (IDI) is commonly used to compare two risk prediction models; it summarizes the extent a new model increases risk in events and decreases risk in non-events. The IDI averages risks across events and non-events and is therefore susceptible to Simpson's paradox. In some settings, adding a predictive covariate to a well calibrated model results in an overall negative (positive) IDI. However, if stratified by that same covariate, the strata-specific IDIs are positive (negative). Meanwhile, the calibration (observed to expected ratio and Hosmer-Lemeshow Goodness of Fit Test), area under the receiver operating characteristic curve, and Brier score improve overall and by stratum. We ran extensive simulations to investigate the impact of an imbalanced covariate upon metrics (IDI, area under the receiver operating characteristic curve, Brier score, and R2), provide an analytic explanation for the paradox in the IDI, and use an investigative metric, a Weighted IDI, to better understand the paradox. In simulations, all instances of the paradox occurred under stratum-specific mis-calibration, yet there were mis-calibrated settings in which the paradox did not occur. The paradox is illustrated on Cancer Genomics Network data by calculating predictions based on two versions of BRCAPRO, a Mendelian risk prediction model for breast and ovarian cancer. In both simulations and the Cancer Genomics Network data, overall model calibration did not guarantee stratum-level calibration. We conclude that the IDI should only assess model performance among a clinically relevant subset when stratum-level calibration is strictly met and recommend calculating additional metrics to confirm the direction and conclusions of the IDI. Copyright © 2016 John Wiley & Sons, Ltd.

Recently, with the development of RNA research techniques, a wide variety of circular RNAs (circRNAs) have been discovered and some of them are confirmed to have crucial biological functions. CircRNAs arise from exons (i.e. exonic circRNAs) or introns (i.e. intronic circRNAs). Acting as microRNA sponges or combining with proteins, circRNAs participate in the regulation of gene expression and influence the activity of some proteins. In addition, some circRNAs even encode proteins. More importantly, several circRNAs play a key role in the occurrence and progression of some tumors, including stomach, liver, colon, breast, cervical, and ovarian cancers. Therefore, circRNAs may be a novel type of diagnostic marker and therapeutic target of cancers.

We examined p16 expression in tumors from a population-based sample of laryngeal cancer cases diagnosed in the U.S. Samples had been previously genotyped for HPV DNA. Overall, p16 expression was observed in laryngeal tissue from 8 of 101 (7.9%) cases. p16 expression was observed in 2 of 16 (12.5%) cases previously determined to be HPV DNA positive. The two cases dually positive for p16 and HPV DNA were non-keratinizing SCC and papillary SCC tumors that were positive for genotypes 18 and 35/89, respectively. Positivity for p16 and/or HPV DNA was not associated with 5-year survival (log-rank p value= 0.55). Our findings support a limited role of HPV in laryngeal carcinogenesis. p16 is not a reliable surrogate for HPV status in laryngeal cancers and is not a predictor of laryngeal cancer survival.

Hepatocellular carcinoma (HCC) is one of the common malignant tumors. HCC gene regulatory network (HCC GRN), whose nodes consist of genes, miRNAs or TFs and whose edges consist of interaction relationships of nodes, is one of the important ways to study molecular mechanism of HCC. Based on various experimental data, types of HCC GRNs could be conducted such as TF-miRNA regulatory network. Integrating the studies of HCC GRN, TF-miRNA transcriptional regulatory network performs better in identifying core genes which play important roles in network disturbances. It is a trend that gene variations and transcriptional regulatory networks should be combined, however the corresponding research is almost blank. This review summarizes the source of HCC data sources, the classification, character, and research program of HCC GRN. Finally, according to present analysis and discussion of progress and research status of HCC GRN, we provide a useful reference for researchers.

Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.

Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell-free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumor-adjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21-gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present in tissue. Digital PCR and mutant allele enrichment before NGS appeared to be more sensitive to detect somatic mutations.

Kaempferol, a natural flavonoid, has been shown to induce cancer cell apoptosis and cell growth inhibition in several tumors. Previously we have conducted a full investigation on the chemical constituents of Gynura medica, kaempferol and its glycosides are the major constituents of G. medica. Here we investigated the growth inhibition and apoptosis induction effect of kaempferol extracted from G. medica.

The aim of this study was to investigate the anti-proliferative effect of Lycopene on HGC-27 cells.

Sijunzi Decoction (SD) is a traditional Chinese medicine which is composed of Ginseng, Atractylodes, Poria and Licorice. It is one of the commonly used Chinese traditional medicines that showed anti-gastric cancer activity in clinical studies. Previous evidence demonstrated SD parties (Ginseng, Atractylodes, Poria, Licorice) can inhibit proliferation and induced apoptosis for gastric cancer cell. In order to further investigate the anticancer effect of SD in gastric cancer, we observed the effects of different concentrations of SD on proliferation and apoptosis of Side Population Cells (SP) of human gastric cancer SGC-7901.

Ovarian cancer is associated with poor survival, because patients are diagnosed at an advanced stage of the disease, and in addition, tumors develop chemoresistance, which carries a poor prognosis for the patient.

Circulating microRNAs (miRNAs) in exosomes are emerging as clinically useful tools for cancer detection. However, little is known about their diagnostic impact in clear-cell renal cell carcinoma (ccRCC).

In men with advanced penile squamous cell carcinoma receiving first-line chemotherapy, visceral metastases (VM) and Eastern Cooperative Oncology Group performance status ≥1 are poor prognostic factors for overall survival (OS). We hypothesized that tumor gene expression profiling may enhance prognostic stratification and identify potential therapeutic targets. In this retrospective study, RNA extracted from macrodissected tumors underwent profiling for the expression of 738 genes using NanoString. Univariate and multivariate analyses assessed the association of genes, VM, and performance status with OS. Tumors were available from 25 men who received first-line cisplatin-based chemotherapy. In univariate analysis, upregulated MAML2 (p=0.004), KITLG (p≤0.0001), and JAK1 (p=0.029) genes were associated with poor OS, and upregulated FANCA was associated with better OS (p=0.024). In stepwise multivariate analyses, VM (hazard ratio=12.75, p=0.0001) and MAML2 (hazard ratio=10.411, p=0.003) were associated with poor OS. The presence of none, one, and both of these poor risk factors was associated with significantly different median OS of 18.4 mo, 7.2 mo, and 2.1 mo, respectively. Unsupervised clustering demonstrated two major molecular subtypes with trend for different survivals (p=0.052). Validation of results is necessary. PATIENT SUMMARY: The expression of the MAML2 gene in penile cancers from men receiving first-line cisplatin-based chemotherapy predicted overall survival independent of clinical factors.

Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts.

The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation. Here we review the impact that epigenetic changes, and specifically DNA methylation, have on these extraordinary sequences in driving cancer progression.

Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.

Recent genome-wide studies of malignancies of the central nervous system (CNS) have revolutionized our understanding of the biology of these tumors. This newly gained knowledge provides a wealth of opportunity for biomarker driven clinical research. To date, however, only few of the available molecular markers truly influence clinical decision-making and treatment. The most widely validated markers in neuro-oncology presently are: 1) MGMT promoter methylation as a prognostic and predictive marker in glioblastoma, 2) co-deletion of 1p and 19q differentiating oligodendrogliomas from astrocytomas, 3) IDH1/2 mutations, and 4) select pathway-associated mutations. This article focuses on currently impactful biomarkers in adult and pediatric brain cancers and it provides a perspective on the direction of research in this field.

Advances in translational research are often driven by new technologies. The advent of microarrays, next-generation sequencing, proteomics and RNA interference (RNAi) have led to breakthroughs in our understanding of the mechanisms of cancer and the discovery of new cancer drug targets. The discovery of the bacterial clustered regularly interspaced palindromic repeat (CRISPR) system and its subsequent adaptation as a tool for mammalian genome engineering has opened up new avenues for functional genomics studies. This review will focus on the utility of CRISPR in the context of cancer drug target discovery.

Immunoglobulin G (IgG) has been implicated in the progression of various cancers. This study explored the role of IgG in the proliferation, apoptosis, cell cycle and in vitro invasive properties of LNCaP prostate cancer cells. We used IGHG1 small interfering RNA to silence IgG1 expression in LNCaP cells. The efficacy of IgG1 gene knockdown was confirmed using qPCR and western blotting. The colony formation, proliferation, migration and invasion abilities of LNCaP cells after transfection were assessed using colony-forming, flow cytometry and transwell assays. The expressions of PCNA and caspase-3 proteins in LNCaP cells after transfection were detected with immunofluorescence staining and western blotting. IgG1 silencing significantly decreased the colony formation, survival, cell cycle progression, migration and invasion of LNCaP cells (p < 0.05). IgG1 silencing also reduced the amount of the proliferation marker PCNA and induced formation of the apoptotic marker caspase-3 (p < 0.05). Our results show that IgG1 produced by LNCaP cells confers advantages for tumor cell survival, proliferation, migration and invasion, suggesting that IgG1 is a potential target for prostate cancer treatment.