Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairs

Hoffman

Genes Chromosomes & Cancer

et al. 2018

Colorectal cancer (CRC) accounts for about 8% of all new cancer cases diagnosed in the US. We used whole exome sequence data from triplet samples (colon carcinoma, colon adenoma, and normal tissue) from 18 individuals to assess gene mutation rates. Of the 2 204 genes that were mutated, APC, TTN, TP53, KRAS, OBSCN, SOX9, PCDH17, SIGLEC10, MYH6, and BRD9 were consistent with genes being an early driver of carcinogenesis, in that they were mutated in multiple adenomas and multiple carcinomas. Fifty‐two genes were mutated in ≥12.5% of microsatellite stable (MSS) carcinomas but not in any of the adenomas, in line with the profile of a late driver event involved in tumor progression. Thirty‐eight genes were sequenced in a larger independent set of 148 carcinoma/normal tissue pairs to obtain more precise mutation frequencies. Eight of the genes, APC, TP53, ATM, CSMD3, LRP1B, RYR2, BIRC6, and MUC17, contained mutations in >20% of the carcinomas. Interestingly, mutations in four genes in addition to APC that are associated with dysregulation of Wnt signaling, were all classified as early driver events. Most of the genes that are commonly associated with colon cancer, including APC, TP53, and KRAS, were all classified as being early driver genes being mutated in both adenomas and carcinomas. Classifying genes as potential early and late driver events points to candidate genes that may help dissect pathways involved in both tumor initiation and progression.

Section: Methodsmentioning

confidence: 99%

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

Hoffman

Genes Chromosomes & Cancer

et al. 2018

Genes Chromosomes & Cancer

“…Local realignments and base‐quality recalibrations were conducted using Genome Analysis Toolkit (GATK) 17, 18. Somatic single‐nucleotide variants (SNVs) and short insertions and deletions (indels) were called using Strelka 19. Functional annotation of the identified somatic variants was implemented by ANNOVAR 20…”

Section: Methodsmentioning

confidence: 99%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

“…Reads were aligned to the human reference genome (hg19) using the BurrowsWheeler Aligner (BWA), 22 followed by realignment and recalibration of the initial alignment using the Genome Analysis Toolkit (GATK). 23 Somatic variants were detected using VarScan2 24 and Strelka 25 (additional details in supplemental Methods). The detected variants by either tool were pooled for follow-up analysis.…”

Section: Wgs Exome and Sanger Sequencing/analysismentioning

confidence: 99%

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

McGirt

Jia

Baerenwald

et al. 2015

Blood

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