VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing

Koboldt, Daniel C.; Zhang, Qunyuan; Larson, David E.; Shen, Dong; McLellan, Michael D.; Li, Gang; Miller, Christopher A.; Mardis, Elaine R.; Li, Ding; Wilson, Richard K.

doi:10.1101/gr.129684.111

Cited by 4,293 publications

(3,624 citation statements)

References 29 publications

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“…Reads were aligned using Novoalign (http://www.novocraft.com/products/novoalign/) and further processed using Picard (http://picard,sourceforge.net/) and the Genome Analysis Tool Kit (GATK) (DePristo et al ., 2011). Somatic variants were called using VarScan2 (Koboldt et al ., 2012). …”

Section: Methodsmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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Section: Methodsmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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“…SAMtools mpileup19 (0.1.19; base phred score >20 and read mapping quality >20, BAQ computation disabled), Varscan220 (v2.4.1; includes running fpfilter.pl) and MuTect21 (v1.1.7) were used to locate non‐reference positions in cell culture, tumor and germline samples. To reduce false positive variant calls, additional filtering was performed.…”

Section: Methodsmentioning

confidence: 99%

Expansion of airway basal epithelial cells from primary human non‐small cell lung cancer tumors

Hynds

Aissa

Gowers

et al. 2018

Intl Journal of Cancer

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Pre‐clinical non‐small cell lung cancer (NSCLC) models are poorly representative of the considerable inter‐ and intra‐tumor heterogeneity of the disease in patients. Primary cell‐based in vitro models of NSCLC are therefore desirable for novel therapy development and personalized cancer medicine. Methods have been described to generate rapidly proliferating epithelial cell cultures from multiple human epithelia using 3T3‐J2 feeder cell culture in the presence of Y‐27632, a RHO‐associated protein kinase (ROCK) inhibitor, in what are known as “conditional reprograming conditions” (CRC) or 3T3 + Y. In some cancer studies, variations of this methodology have allowed primary tumor cell expansion across a number of cancer types but other studies have demonstrated the preferential expansion of normal epithelial cells from tumors in such conditions. Here, we report our experience regarding the derivation of primary NSCLC cell cultures from 12 lung adenocarcinoma patients enrolled in the Tracking Cancer Evolution through Therapy (TRACERx) clinical study and discuss these in the context of improving the success rate for in vitro cultivation of cells from NSCLC tumors.

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“…Applying standard settings, sequences were mapped using the alignment tool BWA (v.0.7.12) 34 . Variant calling was carried out using VarScan 2 (v.2.3.7) 35 with a minimum variant allele frequency (VAF) of 0.5% and variants were annotated using Annovar 36 . Samples from 366 patients enrolled in the UK LRF CLL4 trial were investigated by targeted NGS using a custom design TruSeq gene panel Samples with >5% VAF were considered mutated.…”

Section: Analysis Of Egr2 Mutationsmentioning

confidence: 99%

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

et al. 2016

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EGR2 mutations in CLL 5 AbstractRecurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%), and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

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VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing

Cited by 4,293 publications

References 29 publications

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Expansion of airway basal epithelial cells from primary human non‐small cell lung cancer tumors

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

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