Shimmer: detection of genetic alterations in tumors using next-generation sequence data

Hansen, Nancy F.; Gartner, Jared J.; Lan, Mei; Samuels, Yardena; Mullikin, James C.

doi:10.1093/bioinformatics/btt183

Cited by 60 publications

(45 citation statements)

References 29 publications

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“…Tumor subclonal mutations were detected using Bioconductor package deepSNV version 1.18.1 . Using a beta‐binomial model and a likelihood ratio test, the deepSNV algorithm can discriminate sequencing errors and subclonal SNVs.…”

Section: Methodsmentioning

confidence: 99%

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Cai

Chen

Zeng

et al. 2017

Intl Journal of Cancer

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Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring.Hepatocellular carcinoma (HCC), one of the extraordinarily heterogeneous malignancy diseases, ranks the third leading cause of cancer-related death in China. 1 Unlike most other solid tumors, majority of HCC cases were developed with a history of cirrhosis due to chronic HBV or HCV infections. 2,3 Surgical resection was demonstrated to be the first choice for HCC treatment according to the clinical experiences of the past 50 years. 4 However, the prognosis of HCC remains poor owing to high recurrent/metastatic rate after curative resection, since some of these patients could develop multiple tumor lesions, portal vein tumor thrombus (PVTT), lymph node metastases or other distant metastases. 5,6 The majority

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Section: Methodsmentioning

confidence: 99%

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Cai

Chen

Zeng

et al. 2017

Intl Journal of Cancer

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“…Whole exome sequence reads for each sample were aligned to the hg19 reference sequence using novoalign version 2.08.02 and PCR duplicates were removed using SAMtools (31). We ran Shimmer (19) to perform all-versus-all pairwise comparisons using-minqual 20 and-testall options, and filtering mutation predictions with a read depth of >750 in either sample or a q value of >0.05 as likely artifacts. This resulted in a list of 425 single nucleotide changes and 25 indels for PF1 and 357 single nucleotide changes and 13 indels for PF2 to be interrogated further in the custom capture and sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…The average coverage depth was 88-fold and 63-fold for PF1 and PF2, respectively (PF1 range: 56× to 105×; PF2 range: 54× to 71×). To identify somatic variations in individual daughter lines, we looked for variants that were completely absent in respective parental fibroblasts using Shimmer (19). We identified a wide range of somatic variants in each daughter line, ranging from 39 to 162 putative new variants per line ( Figs.…”

Section: Whole Exome Sequencing Discovered Putative New Variant Daughtermentioning

confidence: 99%

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

Kwon

Connelly

Hansen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs-whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines. Targeted deep sequencing of parental fibroblasts revealed that most variants detected in clonal iPSCs and fibroblast subclones were rare variants inherited from the parental fibroblasts. Only a small number of variants remained undetectable in the parental fibroblasts, which were thus likely to be de novo. Importantly, the clonal iPSCs and fibroblast subclones contained comparable numbers of de novo variants. Collectively, our data suggest that iPSC reprogramming is not mutagenic.iPSCs | fibroblasts | reprogramming | genomic variation | exome sequencing G enomic integrity of human induced pluripotent stem cells (iPSCs) is an unresolved question and a crucial issue for iPSCs-based therapeutics. To understand the scope of acquired genetic changes that occur during iPSC generation, previous studies have compared single nucleotide variants (SNVs), copy number variations (CNVs), and chromosomal rearrangements in iPSCs to donor somatic cells or embryonic stem cells (ESCs) using various assays, including SNP array and next-generation sequencing methods (1-6). Whole genome or exome sequencing (WGS/ WES) of parental and iPSC pairs have demonstrated that there are, on average, 6-12 coding SNVs per iPSC line (1, 7-9) with varying theories regarding when these SNVs arose in the iPSCs. Most reports attributed de novo SNVs or CNVs in iPSCs to reprogramming-induced stress or long-term in vitro culture (2,3,7,8,(10)(11)(12)(13)(14). However, several studies also suggested that many of the "de novo" variants were either inherited rare preexisting variations in the founder source cells or benign variants regardless of reprogramming method used (1,9,15,16).To determine whether iPSCs are inherently more likely to accumulate mutations and further elucidate the origin of genomic variants present in iPSCs, we have undertaken a unique approach by establishing clonal fibroblast subclones and iPSCs from the same fibroblast population to directly assess whether the reprogramming process leads to more mutations by next-generation sequencing. De novo mutations, which were not detected in the starting pooled parental fibroblasts, were identified in each daughter cell line, both fibroblast subclones and iPSCs. These putative de novo mutation sites were then deep sequenced in the parental fibroblast population to determine whether they were present at low frequency as mosaic variants. In addition, highresolution single nucleotide polymorphism (SNP) arrays were used to search for de novo CNVs in both fibrobla...

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“…Seurat27, Shimmer28, Indelocator (http://www.broadinstitute.org/cancer/cga/indelocator), Somatic Sniper29. Strelka30, Varscan 231 and Virmid32.…”

Section: Methodsmentioning

confidence: 99%

Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

Krøigård

Larsen

Brasch‐Andersen

et al. 2017

Sci Rep

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A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.

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Shimmer: detection of genetic alterations in tumors using next-generation sequence data

Cited by 60 publications

References 29 publications

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

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