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BMC Medical Genomics

Bernard Omolo, Mingli Yang, Fang Yin Lo, Michael J Schell, Sharon Austin, Kellie Howard, Anup Madan, Timothy J Yeatman
BACKGROUND: The KRAS gene is mutated in about 40 % of colorectal cancer (CRC) cases, which has been clinically validated as a predictive mutational marker of intrinsic resistance to anti-EGFR inhibitor (EGFRi) therapy. Since nearly 60 % of patients with a wild type KRAS fail to respond to EGFRi combination therapies, there is a need to develop more reliable molecular signatures to better predict response. Here we address the challenge of adapting a gene expression signature predictive of RAS pathway activation, created using fresh frozen (FF) tissues, for use with more widely available formalin fixed paraffin-embedded (FFPE) tissues...
October 19, 2016: BMC Medical Genomics
Lei Wei, Antonios Papanicolau-Sengos, Song Liu, Jianmin Wang, Jeffrey M Conroy, Sean T Glenn, Elizabeth Brese, Qiang Hu, Kiersten Marie Miles, Blake Burgher, Maochun Qin, Karen Head, Angela R Omilian, Wiam Bshara, John Krolewski, Donald L Trump, Candace S Johnson, Carl D Morrison
BACKGROUND: The rapid adoption of next-generation sequencing provides an efficient system for detecting somatic alterations in neoplasms. The detection of such alterations requires a matched non-neoplastic sample for adequate filtering of non-somatic events such as germline polymorphisms. Non-neoplastic tissue adjacent to the excised neoplasm is often used for this purpose as it is simultaneously collected and generally contains the same tissue type as the neoplasm. Following NGS analysis, we and others have frequently observed low-level somatic mutations in these non-neoplastic tissues, which may impose additional challenges to somatic mutation detection as it complicates germline variant filtering...
October 19, 2016: BMC Medical Genomics
Haixu Tang, Xiaoqian Jiang, Xiaofeng Wang, Shuang Wang, Heidi Sofia, Dov Fox, Kristin Lauter, Bradley Malin, Amalio Telenti, Li Xiong, Lucila Ohno-Machado
The outsourcing of genomic data into public cloud computing settings raises concerns over privacy and security. Significant advancements in secure computation methods have emerged over the past several years, but such techniques need to be rigorously evaluated for their ability to support the analysis of human genomic data in an efficient and cost-effective manner. With respect to public cloud environments, there are concerns about the inadvertent exposure of human genomic data to unauthorized users. In analyses involving multiple institutions, there is additional concern about data being used beyond agreed research scope and being prcoessed in untrused computational environments, which may not satisfy institutional policies...
October 13, 2016: BMC Medical Genomics
Glenn S Gerhard, Qunyan Jin, Barbara V Paynton, Steven N Popoff
BACKGROUND: The increasing use of next generation DNA sequencing in clinical medicine is exposing the need for more genetics education in physician training. We piloted an initiative to determine the feasibility of incorporating exome sequencing data generated from DNA obtained from cadavers used for teaching Anatomy into a first year medical student integrated block-style course. METHODS: We optimized the procedure to obtain DNA for exome sequencing by comparing the quality and quantity of DNA isolated from several tissues by two different extraction methods...
October 6, 2016: BMC Medical Genomics
Sunshin Kim, HeeJung Jung, Sung Hee Han, SeungJae Lee, JeongSub Kwon, Min Gyun Kim, Hyungsik Chu, Kyudong Han, Hwanjong Kwak, Sunghoon Park, Hee Jae Joo, Minae An, Jungsu Ha, Kyusang Lee, Byung Chul Kim, Hailing Zheng, Xinqiang Zhu, Hongliang Chen, Jong Bhak
BACKGROUND: Noninvasive prenatal testing (NIPT) using massively parallel sequencing of cell-free DNA (cfDNA) is increasingly being used to predict fetal chromosomal abnormalities. However, concerns over erroneous predictions which occur while performing NIPT still exist in pregnant women at high risk for fetal aneuploidy. We performed the largest-scale clinical NIPT study in Korea to date to assess the risk of false negatives and false positives using next-generation sequencing. METHODS: A total of 447 pregnant women at high risk for fetal aneuploidy were enrolled at 12 hospitals in Korea...
October 3, 2016: BMC Medical Genomics
Subhojit Sen, Kirsten F Block, Alice Pasini, Stephen B Baylin, Hariharan Easwaran
BACKGROUND: Bivalent chromatin refers to overlapping regions containing activating histone H3 Lys4 trimethylation (H3K4me3) and inactivating H3K27me3 marks. Existence of such bivalent marks on the same nucleosome has only recently been suggested. Previous genome-wide efforts to characterize bivalent chromatin have focused primarily on individual marks to define overlapping zones of bivalency rather than mapping positions of truly bivalent mononucleosomes. RESULTS: Here, we developed an efficacious sequential ChIP technique for examining global positioning of individual bivalent nucleosomes...
2016: BMC Medical Genomics
Andréanne Morin, Tony Kwan, Bing Ge, Louis Letourneau, Maria Ban, Karolina Tandre, Maxime Caron, Johanna K Sandling, Jonas Carlsson, Guillaume Bourque, Catherine Laprise, Alexandre Montpetit, Ann-Christine Syvanen, Lars Ronnblom, Stephen J Sawcer, Mark G Lathrop, Tomi Pastinen
BACKGROUND: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq"...
2016: BMC Medical Genomics
Nurul Ainin Abdul Aziz, Norfilza M Mokhtar, Roslan Harun, Md Manir Hossain Mollah, Isa Mohamed Rose, Ismail Sagap, Azmi Mohd Tamil, Wan Zurinah Wan Ngah, Rahman Jamal
BACKGROUND: Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients' survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes' B and C. METHODS: We examined microarray gene expression profiles of 78 archived tissues of patients with Dukes' B and C using the Illumina DASL assay...
2016: BMC Medical Genomics
Ainsley J Newson, Samantha J Leonard, Alison Hall, Clara L Gaff
BACKGROUND: Genomic testing has reached the point where, technically at least, it can be cheaper to undertake panel-, exome- or whole genome testing than it is to sequence a single gene. An attribute of these approaches is that information gleaned will often have uncertain significance. In addition to the challenges this presents for pre-test counseling and informed consent, a further consideration emerges over how - ethically - we should conceive of and respond to this uncertainty. To date, the ethical aspects of uncertainty in genomics have remained under-explored...
2016: BMC Medical Genomics
Chen Du, Barbara N Pusey, Christopher J Adams, C Christopher Lau, William P Bone, William A Gahl, Thomas C Markello, David R Adams
BACKGROUND: Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis...
2016: BMC Medical Genomics
Mikio Watanabe, Chika Honda, Yoshinori Iwatani, Shiro Yorifuji, Hiroyasu Iso, Kei Kamide, Jun Hatazawa, Shinji Kihara, Norio Sakai, Hiroko Watanabe, Kiyoko Makimoto, Mikio Watanabe, Chika Honda, Yoshinori Iwatani
BACKGROUND: DNA methylation levels will be important for detection of epigenetic effects. However, there are few reports showing sex-related differences in the sensitivity to DNA methylation. To evaluate their sex-related individual differences in the sensitivity to methylation rigorously, we performed a systematic analysis of DNA methylation in monozygotic twins, an optimal model to evaluate them because the genetic backgrounds are the same. RESULTS: We examined 30 male and 43 female older monozygotic twin pairs recruited from the registry established by the Center for Twin Research, Osaka University...
2016: BMC Medical Genomics
Mahesh Iddawela, Oscar M Rueda, Marcus Klarqvist, Stefan Graf, Helena M Earl, Carlos Caldas
BACKGROUND: The difficulties in using formalin-fixed and paraffin-embedded (FFPE) tumour specimens for molecular marker studies have hampered progress in translational cancer research. The cDNA-mediated, annealing, selection, extension, and ligation (DASL) assay is a platform for gene expression profiling from FFPE tissue and hence could allow analysis of large collections of tissue with associated clinical data from existing archives, therefore facilitating the development of novel biomarkers...
2016: BMC Medical Genomics
Katsuhiro Omae, Osamu Komori, Shinto Eguchi
BACKGROUND: Detection of disease-associated markers plays a crucial role in gene screening for biological studies. Two-sample test statistics, such as the t-statistic, are widely used to rank genes based on gene expression data. However, the resultant gene ranking is often not reproducible among different data sets. Such irreproducibility may be caused by disease heterogeneity. RESULTS: When we divided data into two subsets, we found that the signs of the two t-statistics were often reversed...
2016: BMC Medical Genomics
Matteo Comin, Michele Schimd
BACKGROUND: Sequencing technologies are generating enormous amounts of read data, however assembly of genomes and metagenomes remain among the most challenging tasks. In this paper we study the comparison of genomes and metagenomes only based on read data, using word counts statistics called alignment-free thus not requiring reference genomes or assemblies. Quality scores produced by sequencing platforms are fundamental for various analyses, moreover future-generation sequencing platforms, will produce longer reads but with error rate around 15 %...
2016: BMC Medical Genomics
Reddy Rani Vangimalla, Hyun-Hwan Jeong, Kyung-Ah Sohn
BACKGROUND: The increasing availability of multiple types of genomic profiles measured from the same cancer patients has provided numerous opportunities for investigating genomic mechanisms underlying cancer. In particular, association studies of gene expression traits with respect to multi-layered genomic features are highly useful for uncovering the underlying mechanism. Conventional correlation-based association tests are limited because they are prone to revealing indirect associations...
2016: BMC Medical Genomics
Anurag Verma, Shefali S Verma, Sarah A Pendergrass, Dana C Crawford, David R Crosslin, Helena Kuivaniemi, William S Bush, Yuki Bradford, Iftikhar Kullo, Suzette J Bielinski, Rongling Li, Joshua C Denny, Peggy Peissig, Scott Hebbring, Mariza De Andrade, Marylyn D Ritchie, Gerard Tromp
BACKGROUND: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy...
2016: BMC Medical Genomics
Kwangsik Nho, Emrin Horgusluoglu, Sungeun Kim, Shannon L Risacher, Dokyoon Kim, Tatiana Foroud, Paul S Aisen, Ronald C Petersen, Clifford R Jack, Leslie M Shaw, John Q Trojanowski, Michael W Weiner, Robert C Green, Arthur W Toga, Andrew J Saykin
BACKGROUND: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics...
2016: BMC Medical Genomics
Chan-Seok Jeong, Dongsup Kim
BACKGROUND: Exome sequencing has been emerged as a primary method to identify detailed sequence variants associated with complex diseases including Crohn's disease in the protein-coding regions of human genome. However, constructing an interpretable model for exome sequencing data is challenging because of the huge diversity of genomic variation. In addition, it has been known that utilizing biologically relevant information in a rigorous manner is essential for effectively extracting disease-associated information...
2016: BMC Medical Genomics
Min Gyun Bae, Jeong Yeon Kim, Jung Kyoon Choi
BACKGROUND: CpG islands (CGIs) are interspersed DNA sequences that have unusually high CpG ratios and GC contents. CGIs are typically located in the promoter of protein-coding genes. They normally lack DNA methylation but become hypermethylated and induce repression of associated genes in cancer. However, the biological functions of non-promoter CGIs (orphan CGIs) largely remain unclear. RESULTS: Here, we identify orphan CGIs that do not map to the promoter of any protein-coding or non-coding transcripts but possess chromatin and transcriptional marks that reflect enhancer activity (termed eCGIs)...
2016: BMC Medical Genomics
Sung-Chou Li, Wen-Ching Chan, Ying-Hsien Huang, Mindy Ming-Huey Guo, Hong-Ren Yu, Fu-Chen Huang, Hsing-Chun Kuo, Ho-Chang Kuo
BACKGROUND: Kawasaki disease (KD) is an autoimmune disease preferentially attacking children younger than five years worldwide. So far, the principal treatment to KD is the administration of Intravenous immunoglobulin (IVIG). Although DNA methylation plays important regulation roles in diseases, few studies investigated the regulation roles of DNA methylation in KD. METHODS: In this study, we focused not only on the DNA methylation alterations resulted from KD onset but also on DNA methylation alterations resulted from IVIG administration...
2016: BMC Medical Genomics
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