MSIsensor: microsatellite instability detection using paired tumor-normal sequence data

Niu, Beifang; Ye, Kai; Zhang, Qunyuan; Lu, Charles; Xie, Mingchao; McLellan, Michael D.; Wendl, Michael C.; Li, Ding

doi:10.1093/bioinformatics/btt755

Cited by 662 publications

(570 citation statements)

References 7 publications

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“…Microsatellite instability (MSI) was assessed for patients with HER2-mutant tumours with matched germline DNA sequencing data (n=89) using an orthogonal bioinformatics tool, MSIsensor 48 . Additionally, mutations were decomposed into the thirty constituent mutational signatures as described previously 49 .…”

Section: Methodsmentioning

confidence: 99%

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

Hyman

Piha-Paul

Won

et al. 2018

Nature

648

545

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Summary Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

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Section: Methodsmentioning

confidence: 99%

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

Hyman

Piha-Paul

Won

et al. 2018

Nature

648

545

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“…Thus, we next sought to assign our CRC case to one of these two subtypes. We used the MSIsensor tool (Niu et al 2014), together with the Illumina WGS data described above, to measure microsatellites in our tumor and adjacent normal control tissues (Methods). The microsatellite mutation rate in our CRC sample (0.01%) was clearly within the MSS range (Niu et al 2014) and was well below the rates observed in tumors that have MSI phenotypes (3.5%-41%).…”

Section: Resultsmentioning

confidence: 99%

“…Using MSIsensor (Niu et al 2014), we determined the total number of somatically mutated microsatellites in our normal/tumor pair plus three control TCGA normal/tumor colorectal cancer pairs in which the microsatellite status was known (two MSS samples and one MSI sample) (The Cancer Genome Atlas Network 2012; data not shown). Cases with <3.5% of microsatellites somatically mutated are considered to have stable microsatellites (MSS), whereas cases with >3.5% of microsatellites somatically mutated are considered to have microsatellite instability (MSI).…”

Section: Microsatellite Assessment Using Msisensormentioning

confidence: 99%

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

et al. 2016

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Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk.

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“…In RTK-altered cases for which mismatch repair protein expression for MLH1, PMS2, MSH2, and MSH6 had not yet been performed, a C++ program called MSI-sensor (7) was used to analyze MSK-IMPACT sequencing data for microsatellite stable versus microsatellite instability–high (MSI-H) status.…”

Section: Methodsmentioning

confidence: 99%

Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF

Hechtman

Zehir

Yaeger

et al. 2016

Molecular Cancer Research

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Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.

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MSIsensor: microsatellite instability detection using paired tumor-normal sequence data

Abstract: https://github.com/ding-lab/msisensor

Cited by 662 publications

References 7 publications

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF

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