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author:("Jia, pailin")
1.  Studying Tumorigenesis through Network Evolution and Somatic Mutational Perturbations in the Cancer Interactome 
Molecular Biology and Evolution  2014;31(8):2156-2169.
Cells govern biological functions through complex biological networks. Perturbations to networks may drive cells to new phenotypic states, for example, tumorigenesis. Identifying how genetic lesions perturb molecular networks is a fundamental challenge. This study used large-scale human interactome data to systematically explore the relationship among network topology, somatic mutation, evolutionary rate, and evolutionary origin of cancer genes. We found the unique network centrality of cancer proteins, which is largely independent of gene essentiality. Cancer genes likely have experienced a lower evolutionary rate and stronger purifying selection than those of noncancer, Mendelian disease, and orphan disease genes. Cancer proteins tend to have ancient histories, likely originated in early metazoan, although they are younger than proteins encoded by Mendelian disease genes, orphan disease genes, and essential genes. We found that the protein evolutionary origin (age) positively correlates with protein connectivity in the human interactome. Furthermore, we investigated the network-attacking perturbations due to somatic mutations identified from 3,268 tumors across 12 cancer types in The Cancer Genome Atlas. We observed a positive correlation between protein connectivity and the number of nonsynonymous somatic mutations, whereas a weaker or insignificant correlation between protein connectivity and the number of synonymous somatic mutations. These observations suggest that somatic mutational network-attacking perturbations to hub genes play an important role in tumor emergence and evolution. Collectively, this work has broad biomedical implications for both basic cancer biology and the development of personalized cancer therapy.
doi:10.1093/molbev/msu167
PMCID: PMC4104318  PMID: 24881052
tumorigenesis; network evolution; network-attacking perturbation; somatic mutation; TCGA
2.  A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance 
Molecular cancer therapeutics  2014;13(7):1918-1928.
Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed “pan-negative”. We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 “pan-negative” melanoma genomes harbored alternate infrequent mutations in the 5 known driver genes along with many mutations in genes encoding guanine nucleotide binding protein α-subunits. Third, we identified 12 significantly mutated genes in “pan-negative” samples (ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including 5 genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least 2 “pan-negative” tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas.
doi:10.1158/1535-7163.MCT-13-0804
PMCID: PMC4090262  PMID: 24755198
Melanoma; Next-generation sequencing; Meta-analysis; Driver mutation; BRAF; NRAS; KIT; GNA11; GNAQ
3.  Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action 
PLoS Computational Biology  2015;11(6):e1004202.
A drug exerts its effects typically through a signal transduction cascade, which is non-linear and involves intertwined networks of multiple signaling pathways. Construction of such a signaling pathway network (SPNetwork) can enable identification of novel drug targets and deep understanding of drug action. However, it is challenging to synopsize critical components of these interwoven pathways into one network. To tackle this issue, we developed a novel computational framework, the Drug-specific Signaling Pathway Network (DSPathNet). The DSPathNet amalgamates the prior drug knowledge and drug-induced gene expression via random walk algorithms. Using the drug metformin, we illustrated this framework and obtained one metformin-specific SPNetwork containing 477 nodes and 1,366 edges. To evaluate this network, we performed the gene set enrichment analysis using the disease genes of type 2 diabetes (T2D) and cancer, one T2D genome-wide association study (GWAS) dataset, three cancer GWAS datasets, and one GWAS dataset of cancer patients with T2D on metformin. The results showed that the metformin network was significantly enriched with disease genes for both T2D and cancer, and that the network also included genes that may be associated with metformin-associated cancer survival. Furthermore, from the metformin SPNetwork and common genes to T2D and cancer, we generated a subnetwork to highlight the molecule crosstalk between T2D and cancer. The follow-up network analyses and literature mining revealed that seven genes (CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway with CDKN1A, SP1, and STK11 might play important roles in metformin’s antidiabetic and anticancer effects. Some results are supported by previous studies. In summary, our study 1) develops a novel framework to construct drug-specific signal transduction networks; 2) provides insights into the molecular mode of metformin; 3) serves a model for exploring signaling pathways to facilitate understanding of drug action, disease pathogenesis, and identification of drug targets.
Author Summary
A deep understanding of a drug’s mechanisms of actions is essential not only in the discovery of new treatments but also in minimizing adverse effects. Here, we develop a computational framework, the Drug-specific Signaling Pathway Network (DSPathNet), to reconstruct a comprehensive signaling pathway network (SPNetwork) impacted by a particular drug. To illustrate this computational approach, we used metformin, an anti-diabetic drug, as an example. Starting from collecting the metformin-related upstream genes and inferring the metformin-related downstream genes, we built one metformin-specific SPNetwork via random walk based algorithms. Our evaluation of the metformin-specific SPNetwork by using disease genes and genotyping data from genome-wide association studies showed that our DSPathNet approach was efficient to synopsize drug’s key components and their relationship involved in the type 2 diabetes and cancer, even the metformin anticancer activity. This work presents a novel computational framework for constructing individual drug-specific signal transduction networks. Furthermore, its successful application to the drug metformin provides some valuable insights into the mode of metformin action, which will facilitate our understanding of the molecular mechanisms underlying drug treatments, disease pathogenesis, and identification of novel drug targets and repurposed drugs.
doi:10.1371/journal.pcbi.1004202
PMCID: PMC4470683  PMID: 26083494
4.  Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1 
Cell reports  2014;7(4):999-1008.
SUMMARY
Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.
doi:10.1016/j.celrep.2014.04.014
PMCID: PMC4074596  PMID: 24813888
5.  NGS Catalog: A Database of Next Generation Sequencing Studies in Humans 
Human mutation  2012;33(6):E2341-E2355.
Next generation sequencing (NGS) technologies have been rapidly applied in biomedical and biological research since its advent only a few years ago, and they are expected to advance at an unprecedented pace in the following years. To provide the research community with a comprehensive NGS resource, we have developed the database Next Generation Sequencing Catalog (NGS Catalog, http://bioinfo.mc.vanderbilt.edu/NGS/index.html), a continually updated database that collects, curates and manages available human NGS data obtained from published literature. NGS Catalog deposits publication information of NGS studies and their mutation characteristics (SNVs, small insertions/deletions, copy number variations, and structural variants), as well as mutated genes and gene fusions detected by NGS. Other functions include user data upload, NGS general analysis pipelines, and NGS software. NGS Catalog is particularly useful for investigators who are new to NGS but would like to take advantage of these powerful technologies for their own research. Finally, based on the data deposited in NGS Catalog, we summarized features and findings from whole exome sequencing, whole genome sequencing, and transcriptome sequencing studies for human diseases or traits.
doi:10.1002/humu.22096
PMCID: PMC4431973  PMID: 22517761
next generation sequencing (NGS); exome sequencing; whole genome sequencing; RNA sequencing; disease genome; gene fusion; database
6.  Clinically relevant genes and regulatory pathways associated with NRASQ61 mutations in melanoma through an integrative genomics approach 
Oncotarget  2014;6(4):2496-2508.
Therapies such as BRAF inhibitors have become standard treatment for melanoma patients whose tumors harbor activating BRAFV600 mutations. However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established. In this study, we performed an integrative analysis of DNA methylation, gene expression, and microRNA expression data to identify potential regulatory pathways associated with the most common driver mutations in NRAS (Q61K/L/R) through comparison of NRASQ61-mutated melanomas with pan-negative melanomas. Surprisingly, we found dominant hypomethylation (98.03%) in NRASQ61-mutated melanomas. We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively. Integrated functional analyses of alterations in all three data types revealed important signaling pathways associated with NRASQ61 mutations, such as the MAPK pathway, as well as other novel cellular processes, such as axon guidance. Further analysis of the relationship between DNA methylation and gene expression changes revealed 9 hypermethylated and down-regulated genes and 112 hypomethylated and up-regulated genes in NRASQ61 melanomas. Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB). Collectively, our observation of predominant gene hypomethylation in NRASQ61 melanomas and the identification of NRASQ61-linked pathways will be useful for the development of targeted therapies against melanomas harboring NRASQ61 mutations.
PMCID: PMC4385866  PMID: 25537510
NRAS; melanoma; driver mutation; DNA methylation; gene expression; regulatory pathway
7.  VERSE: a novel approach to detect virus integration in host genomes through reference genome customization 
Genome Medicine  2015;7(1):2.
Fueled by widespread applications of high-throughput next generation sequencing (NGS) technologies and urgent need to counter threats of pathogenic viruses, large-scale studies were conducted recently to investigate virus integration in host genomes (for example, human tumor genomes) that may cause carcinogenesis or other diseases. A limiting factor in these studies, however, is rapid virus evolution and resulting polymorphisms, which prevent reads from aligning readily to commonly used virus reference genomes, and, accordingly, make virus integration sites difficult to detect. Another confounding factor is host genomic instability as a result of virus insertions. To tackle these challenges and improve our capability to identify cryptic virus-host fusions, we present a new approach that detects Virus intEgration sites through iterative Reference SEquence customization (VERSE). To the best of our knowledge, VERSE is the first approach to improve detection through customizing reference genomes. Using 19 human tumors and cancer cell lines as test data, we demonstrated that VERSE substantially enhanced the sensitivity of virus integration site detection. VERSE is implemented in the open source package VirusFinder 2 that is available at http://bioinfo.mc.vanderbilt.edu/VirusFinder/.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-015-0126-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-015-0126-6
PMCID: PMC4333248  PMID: 25699093
8.  Protein-Protein Interaction and Pathway Analyses of Top Schizophrenia Genes Reveal Schizophrenia Susceptibility Genes Converge on Common Molecular Networks and Enrichment of Nucleosome (Chromatin) Assembly Genes in Schizophrenia Susceptibility Loci 
Schizophrenia Bulletin  2013;40(1):39-49.
Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.
doi:10.1093/schbul/sbt066
PMCID: PMC3885298  PMID: 23671194
genome-wide association study; schizophrenia susceptibility genes; protein-protein interaction; common molecular networks; genetic heterogeneity; enrichment
9.  Key regulators in prostate cancer identified by co-expression module analysis 
BMC Genomics  2014;15:1015.
Background
Prostate cancer (PrCa) is the most commonly diagnosed cancer in men in the world. Despite the fact that a large number of its genes have been investigated, its etiology remains poorly understood. Furthermore, most PrCa candidate genes have not been rigorously replicated, and the methods by which they biologically function in PrCa remain largely unknown.
Results
Aiming to identify key players in the complex prostate cancer system, we reconstructed PrCa co-expressed modules within functional gene sets defined by the Gene Ontology (GO) annotation (biological process, GO_BP). We primarily identified 118 GO_BP terms that were well-preserved between two independent gene expression datasets and a consequent 55 conserved co-expression modules within them. Five modules were then found to be significantly enriched with PrCa candidate genes collected from expression Quantitative Trait Loci (eQTL), somatic copy number alteration (SCNA), somatic mutation data, or prognostic analyses. Specifically, two transcription factors (TFs) (NFAT and SP1) and three microRNAs (hsa-miR-19a, hsa-miR-15a, and hsa-miR-200b) regulating these five candidate modules were found to be critical to the development of PrCa.
Conclusions
Collectively, our results indicated that genes with similar functions may play important roles in disease through co-expression, and modules with different functions could be regulated by similar genetic components, such as TFs and microRNAs, in a synergistic manner.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1015) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1015
PMCID: PMC4258300  PMID: 25418933
Prostate cancer; Co-expression; Gene Ontology; Module; Transcription factor; MicroRNA
10.  MSEA: detection and quantification of mutation hotspots through mutation set enrichment analysis 
Genome Biology  2014;15(10):489.
Many cancer genes form mutation hotspots that disrupt their functional domains or active sites, leading to gain- or loss-of-function. We propose a mutation set enrichment analysis (MSEA) implemented by two novel methods, MSEA-clust and MSEA-domain, to predict cancer genes based on mutation hotspot patterns. MSEA methods are evaluated by both simulated and real cancer data. We find approximately 51% of the eligible known cancer genes form detectable mutation hotspots. Application of MSEA in eight cancers reveals a total of 82 genes with mutation hotspots, including well-studied cancer genes, known cancer genes re-found in new cancer types, and novel cancer genes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0489-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0489-9
PMCID: PMC4226881  PMID: 25348067
11.  Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy 
PLoS ONE  2014;9(8):e103123.
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
doi:10.1371/journal.pone.0103123
PMCID: PMC4140681  PMID: 25144566
12.  Top associated SNPs in prostate cancer are significantly enriched in cis-expression quantitative trait loci and at transcription factor binding sites 
Oncotarget  2014;5(15):6168-6177.
While genome-wide association studies (GWAS) have revealed thousands of disease risk single nucleotide polymorphisms (SNPs), their functions remain largely unknown. Recent studies have suggested the regulatory roles of GWAS risk variants in several common diseases; however, the complex regulatory structure in prostate cancer is unclear.
We investigated the potential regulatory roles of risk variants in two prostate cancer GWAS datasets by their interactions with expression quantitative trait loci (eQTL) and/or transcription factor binding sites (TFBSs) in three populations.
Our results indicated that the moderately associated GWAS SNPs were significantly enriched with cis-eQTLs and TFBSs in Caucasians (CEU), but not in African Americans (AA) or Japanese (JPT); this was also observed in an independent pan-cancer related SNPs from the GWAS Catalog. We found that the eQTL enrichment in the CEU population was tissue-specific to eQTLs from CEU lymphoblastoid cell lines. Importantly, we pinpointed two SNPs, rs2861405 and rs4766642, by overlapping results from cis-eQTL and TFBS as applied to the CEU data.
These results suggested that prostate cancer associated SNPs and pan-cancer associated SNPs are likely to play regulatory roles in CEU. However, the negative enrichment results in AA or JPT and the potential mechanisms remain to be elucidated in additional samples.
PMCID: PMC4171620  PMID: 25026280
prostate cancer; genome-wide association studies; eQTL; TFBS; regulatory variants
13.  Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia 
Schizophrenia research  2011;131(0):43-51.
We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r2>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10×10−3 and rs2274736, P=1.21×10−3). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86–0.97, P=5.45×10−3 and rs2401751, OR = 0.92, 95% CI: 0.86–0.97, P=5.29×10−3). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR = 1.08, 95% CI: 1.02-1.14, P=6.43×10−3). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.
doi:10.1016/j.schres.2011.06.023
PMCID: PMC4117700  PMID: 21752600
Data-mining; Informatic prioritization; Genetic association study; PTPN21; Non-synonymous SNP
14.  Application of next generation sequencing to human gene fusion detection: computational tools, features and perspectives 
Briefings in Bioinformatics  2012;14(4):506-519.
Gene fusions are important genomic events in human cancer because their fusion gene products can drive the development of cancer and thus are potential prognostic tools or therapeutic targets in anti-cancer treatment. Major advancements have been made in computational approaches for fusion gene discovery over the past 3 years due to improvements and widespread applications of high-throughput next generation sequencing (NGS) technologies. To identify fusions from NGS data, existing methods typically leverage the strengths of both sequencing technologies and computational strategies. In this article, we review the NGS and computational features of existing methods for fusion gene detection and suggest directions for future development.
doi:10.1093/bib/bbs044
PMCID: PMC3713712  PMID: 22877769
gene fusion; next generation sequencing; cancer; whole genome sequencing; transcriptome sequencing; computational tools
15.  Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma 
Cancer  2013;119(11):1985-1993.
Background
MicroRNAs (miRNAs) play critical roles in tumor development and progression. The fact that a single miRNA can regulate hundreds of genes places miRNAs at critical hubs of signaling pathways. In this study, we investigated the miRNA expression profile in gastric adenocarcinomas and compared it to esophageal adenocarcinomas to better identify a unique miRNA signature of gastric adenocarcinoma.
Methods and Results
The miRNA expression profile was obtained using Agilent and Exiqon microarray platforms on primary gastric adenocarcinoma tissue samples. The cross comparison of results identified 17 up-regulated and 12 down-regulated miRNAs that overlapped in both platforms. Quantitative real-time RT-PCR was performed for independent validation of a representative set of 8 miRNAs in gastric and esophageal adenocarcinomas as compared to normal gastric mucosa or esophageal mucosa, respectively. The de-regulation of miR-146b-5p, -375, -148a, -31, and -451 was significantly associated with gastric adenocarcinomas. On the other hand, de-regulation of miR-21 (up-regulation) and miR-133b (down-regulation) was detectable in both gastric and esophageal adenocarcinomas. Interestingly, miR-200a was significantly down-regulated in gastric adenocarcinoma (p=0.04) but up-regulated in esophageal adenocarcinoma samples (p=0.001). In addition, the expression level of miR-146b-5p displayed a strong correlation with the tumor staging of gastric cancer.
Conclusion
Gastric adenocarcinoma displays a unique miRNA signature that distinguishes it from esophageal adenocarcinoma. This specific signature could reflect differences in the etiology and/or molecular signaling in these two closely related cancers. Our findings suggest important miRNA candidates that can be investigated for their molecular functions and possible diagnostic, prognostic, and therapeutic role in gastric adenocarcinoma.
doi:10.1002/cncr.28002
PMCID: PMC3731210  PMID: 23456798
miRNA; esophageal adenocarcinoma; gastric adenocarcinoma; microarray; prognosis
16.  Quantitative network mapping of the human kinome interactome reveals new clues for rational kinase inhibitor discovery and individualized cancer therapy 
Oncotarget  2014;5(11):3697-3710.
The human kinome is gaining importance through its promising cancer therapeutic targets, yet no general model to address the kinase inhibitor resistance has emerged. Here, we constructed a systems biology-based framework to catalogue the human kinome, including 538 kinase genes, in the broader context of the human interactome. Specifically, we constructed three networks: a kinase-substrate interaction network containing 7,346 pairs connecting 379 kinases to 36,576 phosphorylation sites in 1,961 substrates, a protein-protein interaction network (PPIN) containing 92,699 pairs, and an atomic resolution PPIN containing 4,278 pairs. We identified the conserved regulatory phosphorylation motifs (e.g., Ser/Thr-Pro) using a sequence logo analysis. We found the typical anticancer target selection strategy that uses network hubs as drug targets, might lead to a high adverse drug reaction risk. Furthermore, we found the distinct network centrality of kinases creates a high anticancer drug resistance risk by feedback or crosstalk mechanisms within cellular networks. This notion is supported by the systematic network and pathway analyses that anticancer drug resistance genes are significantly enriched as hubs and heavily participate in multiple signaling pathways. Collectively, this comprehensive human kinome interactome map sheds light on anticancer drug resistance mechanisms and provides an innovative resource for rational kinase inhibitor design.
PMCID: PMC4116514  PMID: 25003367
Kinome; kinase-substrate interaction; phosphorylation; interactome; resistance; systems biology
17.  Network and Pathway Analysis of Cancer Susceptibility (A) 
Cancer Informatics  2014;13(Suppl 5):125-127.
doi:10.4137/CIN.S24095
PMCID: PMC4364546  PMID: 25861212
18.  Patterns and processes of somatic mutations in nine major cancers 
BMC Medical Genomics  2014;7:11.
Background
Cancer genomes harbor hundreds to thousands of somatic nonsynonymous mutations. DNA damage and deficiency of DNA repair systems are two major forces to cause somatic mutations, marking cancer genomes with specific somatic mutation patterns. Recently, several pan-cancer genome studies revealed more than 20 mutation signatures across multiple cancer types. However, detailed cancer-type specific mutation signatures and their different features within (intra-) and between (inter-) cancer types remain largely unexplored.
Methods
We employed a matrix decomposition algorithm, namely Non-negative Matrix Factorization, to survey the somatic mutations in nine major human cancers, involving a total of ~2100 genomes.
Results
Our results revealed 3-5 independent mutational signatures in each cancer, implying that a range of 3-5 predominant mutational processes likely underlie each cancer genome. Both mutagen exposure (tobacco and sun) and changes in DNA repair systems (APOBEC family, POLE, and MLH1) were found as mutagenesis forces, each of which marks the genome with an evident mutational signature. We studied the features of several signatures and their combinatory patterns within and across cancers. On one hand, we found each signature may influence a cancer genome with different influential magnitudes even in the same cancer type and the signature-specific load reflects intra-cancer heterogeneity (e.g., the smoking-related signature in lung cancer smokers and never smokers). On the other hand, inter-cancer heterogeneity is characterized by combinatory patterns of mutational signatures, where no cancers share the same signature profile, even between two lung cancer subtypes (lung adenocarcinoma and squamous cell lung cancer).
Conclusions
Our work provides a detailed overview of the mutational characteristics in each of nine major cancers and highlights that the mutational signature profile is representative of each cancer.
doi:10.1186/1755-8794-7-11
PMCID: PMC3942057  PMID: 24552141
Somatic mutation; Cancer; Kataegis; Mutation signature; Mutagen; Heterogeneity
19.  VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data 
PLoS Computational Biology  2014;10(2):e1003460.
A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.
Author Summary
A cancer genome typically harbors both driver mutations, which contribute to tumorigenesis, and passenger mutations, which tend to be neutral and occur randomly. Cancer genomes differ dramatically due to genetic and environmental factors. A major challenge in interpreting the large volume of mutation data identified in cancer genomes using next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. Applying our approach in a large cohort of lung adenocarcinoma samples and melanoma samples, we derived a consensus mutation subnetwork for each cancer containing significantly enriched cancer genes and cancer-related functional pathways. Our results indicated that driver genes occur within a broad spectrum of frequency, interact with each other, and converge in several key pathways that play critical roles in tumorigenesis.
doi:10.1371/journal.pcbi.1003460
PMCID: PMC3916227  PMID: 24516372
20.  Gene set analysis of genome-wide association studies: methodological issues and perspectives 
Genomics  2011;98(1):10.1016/j.ygeno.2011.04.006.
Recent studies have demonstrated that gene set analysis, which tests disease association with genetic variants in a group of functionally related genes, is a promising approach for analyzing and interpreting genome-wide association studies (GWAS) data. These approaches aim to increase power by combining association signals from multiple genes in the same gene set. In addition, gene set analysis can also shed more light on the biological processes underlying complex diseases. However, current approaches for gene set analysis are still in an early stage of development in that analysis results are often prone to sources of bias, including gene set size and gene length, linkage disequilibrium patterns and the presence of overlapping genes. In this paper, we provide an in-depth review of the gene set analysis procedures, along with parameter choices and the particular methodology challenges at each stage. In addition to providing a survey of recently developed tools, we also classify the analysis methods into larger categories and discuss their strengths and limitations. In the last section, we outline several important areas for improving the analytical strategies in gene set analysis.
doi:10.1016/j.ygeno.2011.04.006
PMCID: PMC3852939  PMID: 21565265
Genome-wide association study; Gene set; Pathway; Gene-set enrichment analysis; Statistical significance; Complex disease
21.  Multi-Dimensional Prioritization of Dental Caries Candidate Genes and Its Enriched Dense Network Modules 
PLoS ONE  2013;8(10):e76666.
A number of genetic studies have suggested numerous susceptibility genes for dental caries over the past decade with few definite conclusions. The rapid accumulation of relevant information, along with the complex architecture of the disease, provides a challenging but also unique opportunity to review and integrate the heterogeneous data for follow-up validation and exploration. In this study, we collected and curated candidate genes from four major categories: association studies, linkage scans, gene expression analyses, and literature mining. Candidate genes were prioritized according to the magnitude of evidence related to dental caries. We then searched for dense modules enriched with the prioritized candidate genes through their protein-protein interactions (PPIs). We identified 23 modules comprising of 53 genes. Functional analyses of these 53 genes revealed three major clusters: cytokine network relevant genes, matrix metalloproteinases (MMPs) family, and transforming growth factor-beta (TGF-β) family, all of which have been previously implicated to play important roles in tooth development and carious lesions. Through our extensive data collection and an integrative application of gene prioritization and PPI network analyses, we built a dental caries-specific sub-network for the first time. Our study provided insights into the molecular mechanisms underlying dental caries. The framework we proposed in this work can be applied to other complex diseases.
doi:10.1371/journal.pone.0076666
PMCID: PMC3795720  PMID: 24146904
22.  Detecting somatic point mutations in cancer genome sequencing data: a comparison of mutation callers 
Genome Medicine  2013;5(10):91.
Background
Driven by high throughput next generation sequencing technologies and the pressing need to decipher cancer genomes, computational approaches for detecting somatic single nucleotide variants (sSNVs) have undergone dramatic improvements during the past 2 years. The recently developed tools typically compare a tumor sample directly with a matched normal sample at each variant locus in order to increase the accuracy of sSNV calling. These programs also address the detection of sSNVs at low allele frequencies, allowing for the study of tumor heterogeneity, cancer subclones, and mutation evolution in cancer development.
Methods
We used whole genome sequencing (Illumina Genome Analyzer IIx platform) of a melanoma sample and matched blood, whole exome sequencing (Illumina HiSeq 2000 platform) of 18 lung tumor-normal pairs and seven lung cancer cell lines to evaluate six tools for sSNV detection: EBCall, JointSNVMix, MuTect, SomaticSniper, Strelka, and VarScan 2, with a focus on MuTect and VarScan 2, two widely used publicly available software tools. Default/suggested parameters were used to run these tools. The missense sSNVs detected in these samples were validated through PCR and direct sequencing of genomic DNA from the samples. We also simulated 10 tumor-normal pairs to explore the ability of these programs to detect low allelic-frequency sSNVs.
Results
Out of the 237 sSNVs successfully validated in our cancer samples, VarScan 2 and MuTect detected the most of any tools (that is, 204 and 192, respectively). MuTect identified 11 more low-coverage validated sSNVs than VarScan 2, but missed 11 more sSNVs with alternate alleles in normal samples than VarScan 2. When examining the false calls of each tool using 169 invalidated sSNVs, we observed >63% false calls detected in the lung cancer cell lines had alternate alleles in normal samples. Additionally, from our simulation data, VarScan 2 identified more sSNVs than other tools, while MuTect characterized most low allelic-fraction sSNVs.
Conclusions
Our study explored the typical false-positive and false-negative detections that arise from the use of sSNV-calling tools. Our results suggest that despite recent progress, these tools have significant room for improvement, especially in the discrimination of low coverage/allelic-frequency sSNVs and sSNVs with alternate alleles in normal samples.
doi:10.1186/gm495
PMCID: PMC3971343  PMID: 24112718
23.  Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives 
BMC Bioinformatics  2013;14(Suppl 11):S1.
Copy number variation (CNV) is a prevalent form of critical genetic variation that leads to an abnormal number of copies of large genomic regions in a cell. Microarray-based comparative genome hybridization (arrayCGH) or genotyping arrays have been standard technologies to detect large regions subject to copy number changes in genomes until most recently high-resolution sequence data can be analyzed by next-generation sequencing (NGS). During the last several years, NGS-based analysis has been widely applied to identify CNVs in both healthy and diseased individuals. Correspondingly, the strong demand for NGS-based CNV analyses has fuelled development of numerous computational methods and tools for CNV detection. In this article, we review the recent advances in computational methods pertaining to CNV detection using whole genome and whole exome sequencing data. Additionally, we discuss their strengths and weaknesses and suggest directions for future development.
doi:10.1186/1471-2105-14-S11-S1
PMCID: PMC3846878  PMID: 24564169
24.  BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors 
Cancer discovery  2012;2(9):791-797.
Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40–50% of cases are positive. To uncover other potential targetable mutations, we performed whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, D816) wildtype melanoma. Surprisingly, we found a somatic BRAF L597R mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF V600 mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that 2 (4%) harbored L597 mutations and another 2 involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by MEK inhibition. A patient with BRAF L597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data demonstrate clinical significance to BRAF L597 mutations in melanoma.
doi:10.1158/2159-8290.CD-12-0097
PMCID: PMC3449158  PMID: 22798288
melanoma; BRAF L597; whole genome sequencing; BRAF inhibitor; MEK inhibitor; TAK-733
25.  Association Signals Unveiled by a Comprehensive Gene Set Enrichment Analysis of Dental Caries Genome-Wide Association Studies 
PLoS ONE  2013;8(8):e72653.
Gene set-based analysis of genome-wide association study (GWAS) data has recently emerged as a useful approach to examine the joint effects of multiple risk loci in complex human diseases or phenotypes. Dental caries is a common, chronic, and complex disease leading to a decrease in quality of life worldwide. In this study, we applied the approaches of gene set enrichment analysis to a major dental caries GWAS dataset, which consists of 537 cases and 605 controls. Using four complementary gene set analysis methods, we analyzed 1331 Gene Ontology (GO) terms collected from the Molecular Signatures Database (MSigDB). Setting false discovery rate (FDR) threshold as 0.05, we identified 13 significantly associated GO terms. Additionally, 17 terms were further included as marginally associated because they were top ranked by each method, although their FDR is higher than 0.05. In total, we identified 30 promising GO terms, including ‘Sphingoid metabolic process,’ ‘Ubiquitin protein ligase activity,’ ‘Regulation of cytokine secretion,’ and ‘Ceramide metabolic process.’ These GO terms encompass broad functions that potentially interact and contribute to the oral immune response related to caries development, which have not been reported in the standard single marker based analysis. Collectively, our gene set enrichment analysis provided complementary insights into the molecular mechanisms and polygenic interactions in dental caries, revealing promising association signals that could not be detected through single marker analysis of GWAS data.
doi:10.1371/journal.pone.0072653
PMCID: PMC3743773  PMID: 23967329

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