%0 Journal Article %J BMC Genomics %D 2017 %T SVachra: a tool to identify genomic structural variation in mate pair sequencing data containing inward and outward facing reads. %A Hampton, Oliver A %A English, Adam C %A Wang, Mark %A Salerno, William J %A Liu, Yue %A Muzny, Donna M %A Han, Yi %A Wheeler, David A %A Worley, Kim C %A Lupski, James R %A Gibbs, Richard A %K Genetic Variation %K Genomics %K Sequence Analysis, DNA %X

BACKGROUND: Characterization of genomic structural variation (SV) is essential to expanding the research and clinical applications of genome sequencing. Reliance upon short DNA fragment paired end sequencing has yielded a wealth of single nucleotide variants and internal sequencing read insertions-deletions, at the cost of limited SV detection. Multi-kilobase DNA fragment mate pair sequencing has supplemented the void in SV detection, but introduced new analytic challenges requiring SV detection tools specifically designed for mate pair sequencing data. Here, we introduce SVachra - Structural Variation Assessment of CHRomosomal Aberrations, a breakpoint calling program that identifies large insertions-deletions, inversions, inter- and intra-chromosomal translocations utilizing both inward and outward facing read types generated by mate pair sequencing.

RESULTS: We demonstrate SVachra's utility by executing the program on large-insert (Illumina Nextera) mate pair sequencing data from the personal genome of a single subject (HS1011). An additional data set of long-read (Pacific BioSciences RSII) was also generated to validate SV calls from SVachra and other comparison SV calling programs. SVachra exhibited the highest validation rate and reported the widest distribution of SV types and size ranges when compared to other SV callers.

CONCLUSIONS: SVachra is a highly specific breakpoint calling program that exhibits a more unbiased SV detection methodology than other callers.

%B BMC Genomics %V 18 %P 691 %8 2017 Oct 03 %G eng %N Suppl 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28984202?dopt=Abstract %R 10.1186/s12864-017-4021-y %0 Journal Article %J Nature %D 2014 %T Novel somatic and germline mutations in intracranial germ cell tumours. %A Wang, Linghua %A Yamaguchi, Shigeru %A Burstein, Matthew D %A Terashima, Keita %A Chang, Kyle %A Ng, Ho-Keung %A Nakamura, Hideo %A He, Zongxiao %A Doddapaneni, Harshavardhan %A Lewis, Lora %A Wang, Mark %A Suzuki, Tomonari %A Nishikawa, Ryo %A Natsume, Atsushi %A Terasaka, Shunsuke %A Dauser, Robert %A Whitehead, William %A Adekunle, Adesina %A Sun, Jiayi %A Qiao, Yi %A Marth, Gábor %A Muzny, Donna M %A Gibbs, Richard A %A Leal, Suzanne M %A Wheeler, David A %A Lau, Ching C %K Adult %K Brain Neoplasms %K Child %K Female %K Germ-Line Mutation %K Humans %K Japan %K Male %K Mutation %K Neoplasms, Germ Cell and Embryonal %K Oncogene Protein v-akt %K Proto-Oncogene Proteins c-kit %K ras Proteins %K Reproducibility of Results %K Signal Transduction %K TOR Serine-Threonine Kinases %K Young Adult %X

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

%B Nature %V 511 %P 241-5 %8 2014 Jul 10 %G eng %N 7508 %1 https://www.ncbi.nlm.nih.gov/pubmed/24896186?dopt=Abstract %R 10.1038/nature13296