Dataset Information

MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations.

ABSTRACT: Microsatellite instability (MSI) is a form of hypermutation that occurs in some tumors due to defects in cellular DNA mismatch repair. MSI is characterized by frequent somatic mutations (i.e., cancer-specific mutations) that change the length of simple repeats (e.g., AAAAA…., GATAGATAGATA...). Clinical MSI tests evaluate the lengths of a handful of simple repeat sites, while next-generation sequencing can assay many more sites and offers a much more complete view of their somatic mutation frequencies. Using somatic mutation data from the exomes of a 361-tumor training set, we developed classifiers to determine MSI status based on four machine-learning frameworks. All frameworks had high accuracy, and after choosing one we determined that it had >98% concordance with clinical tests in a separate 163-tumor test set. Furthermore, this classifier retained high concordance even when classifying tumors based on subsets of whole-exome data. We have released a CRAN R package, MSIseq, based on this classifier. MSIseq is faster and simpler to use than software that requires large files of aligned sequenced reads. MSIseq will be useful for genomic studies in which clinical MSI test results are unavailable and for detecting possible misclassifications by clinical tests.

SUBMITTER: Huang MN

PROVIDER: S-EPMC4549793 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations.

Huang Mi Ni MN McPherson John R JR Cutcutache Ioana I Teh Bin Tean BT Tan Patrick P Rozen Steven G SG

Scientific reports 20150826

Microsatellite instability (MSI) is a form of hypermutation that occurs in some tumors due to defects in cellular DNA mismatch repair. MSI is characterized by frequent somatic mutations (i.e., cancer-specific mutations) that change the length of simple repeats (e.g., AAAAA…., GATAGATAGATA...). Clinical MSI tests evaluate the lengths of a handful of simple repeat sites, while next-generation sequencing can assay many more sites and offers a much more complete view of their somatic mutation freque ...[more]

PMID: 26306458

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Project description:Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (≥30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients' outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients.

Project description:BackgroundThe fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor.Aim and methodsThus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect.ResultsAs expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]).ConclusionsIn contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors.

Dataset Information

MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations.

Publications

MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations.

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