Biology subjects

Iyer, A.

Publications and source records attributed to Iyer, A..

3 recordsLinked to original sources

bioRxiv2018

Clonotypic Heterogeneity In Cutaneous T-Cell Lymphoma Revealed By Comprehensive Whole Exome/Transcriptome Sequencing

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin resident memory T-cell. T-cell receptor (TCR) clonality (i.e. identical sequences of rearranged TCR, {beta} and {gamma}), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor infiltrating, reactive lymphocytes, which contribute to the TCR clonotypic repertoire of MF. Here we have successfully adopted the technique of targeted whole exome and whole transcriptome sequencing (WES/WTS) to identify the repertoire of rearranged TCR genes in tumor enriched samples from patients with MF. Although most of the investigated biopsies of MF had the expected monoclonal rearrangements of TCR{gamma} of the frequency corresponding to the frequency of tumor cells, in half of the samples we detected multiple (up to seven) TCR and -{beta} clonotypes by WES and WTS. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature, memory T-cells but rather at the level of T-lymphocyte progenitor after TCR{gamma} rearrangement but before TCR{beta} or TCR rearrangements. The WES/WTS method is potentially applicable to other types of T-cell lymphomas and enables comprehensive characterization of the TCR repertoire and mutational landscape in these malignancies.

cancer biology↗

bioRxiv2018

Elucidating synergistic dependencies in lung adenocarcinoma by proteome-wide signaling-network analysis

Signaling pathway models are largely based on the compilation of literature data from heterogeneous cellular contexts. Indeed, de novo reconstruction of signaling interactions from large-scale molecular profiling is still lagging, compared to similar efforts in transcriptional and protein-protein interaction networks. To address this challenge, we introduce a novel algorithm for the systematic inference of protein kinase pathways, and applied it to published mass spectrometry-based phosphotyrosine profile data from 250 lung adenocarcinoma (LUAD) samples. The resulting network includes 43 TKs and 415 inferred, LUAD-specific substrates, which were validated at >60% accuracy by SILAC assays, including \"novel substrates of the EGFR and c-MET TKs, which play a critical oncogenic role in lung cancer. This systematic, data-driven model supported drug response prediction on an individual sample basis, including accurate prediction and validation of synergistic EGFR and c-MET inhibitor activity in cells lacking mutations in either gene, thus contributing to current precision oncology efforts.

systems biology↗

bioRxiv2018

Pisces: An Accurate and Versatile Variant Caller for Somatic and Germline Next-Generation Sequencing Data

MotivationNext-Generation Sequencing (NGS) technology is transitioning quickly from research labs to clinical settings. The diagnosis and treatment selection for many acquired and autosomal conditions necessitate a method for accurately detecting somatic and germline variants, suitable for the clinic.\n\nResultsWe have developed Pisces, a rapid, versatile and accurate small variant calling suite designed for somatic and germline amplicon sequencing applications. Pisces accuracy is achieved by four distinct modules, the Pisces Read Stitcher, Pisces Variant Caller, the Pisces Variant Quality Recalibrator, and the Pisces Variant Phaser. Each module incorporates a number of novel algorithmic strategies aimed at reducing noise or increasing the likelihood of detecting a true variant.\n\nAvailabilityPisces is distributed under an open source license and can be downloaded from https://github.com/Illumina/Pisces. Pisces is available on the BaseSpace SequenceHub as part of the TruSeq Amplicon workflow and the Illumina Ampliseq Workflow. Pisces is distributed on Illumina sequencing platforms such as the MiSeq, and is included in the Praxis Extended RAS Panel test which was recently approved by the FDA for the detection of multiple RAS gene mutations.\n\nContactpisces@illumina.com\n\nSupplementary informationSupplementary data are available online.

bioinformatics↗