Biology subjects

Sabarinathan, R.

Publications and source records attributed to Sabarinathan, R..

4 recordsLinked to original sources

bioRxiv2018

The Repertoire of Mutational Signatures in Human Cancer

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

cancer biology↗

bioRxiv2017

Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes

Discovery of cancer drivers has traditionally focused on the identification of protein-coding genes. Here we present a comprehensive analysis of putative cancer driver mutations in both protein-coding and non-coding genomic regions across >2,500 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We developed a statistically rigorous strategy for combining significance levels from multiple driver discovery methods and demonstrate that the integrated results overcome limitations of individual methods. We combined this strategy with careful filtering and applied it to protein-coding genes, promoters, untranslated regions (UTRs), distal enhancers and non-coding RNAs. These analyses redefine the landscape of non-coding driver mutations in cancer genomes, confirming a few previously reported elements and raising doubts about others, while identifying novel candidate elements across 27 cancer types. Novel recurrent events were found in the promoters or 5UTRs of TP53, RFTN1, RNF34, and MTG2, in the 3UTRs of NFKBIZ and TOB1, and in the non-coding RNA RMRP. We provide evidence that the previously reported non-coding RNAs NEAT1 and MALAT1 may be subject to a localized mutational process. Perhaps the most striking finding is the relative paucity of point mutations driving cancer in non-coding genes and regulatory elements. Though we have limited power to discover infrequent non-coding drivers in individual cohorts, combined analysis of promoters of known cancer genes show little excess of mutations beyond TERT.

genomics↗

bioRxiv2017

A pan-cancer landscape of interactions between solid tumors and infiltrating immune cell populations

Throughout their development, tumors are challenged by the immune system and acquire features to evade its surveillance. A systematic view of these traits is still lacking. Here, we identify genomic and transcriptomic traits associated to the immune-phenotype of 9,403 tumors of 29 solid cancers. In highly cytotoxic immune-phenotypes we found tumors with low clonal heterogeneity enriched by alterations of genes involved in epigenetic regulation, ubiquitin mediated proteolysis, antigen-presentation and cell-cell communication, which may drive resistance. Tumors with immune-phenotypes with mid cytotoxicity present an over-activation of processes involved in invasion and remodeling of neighboring tissues that may foster the recruitment of immune-suppressive cells. Tumors with poor cytotoxic immune-phenotype tend to be of more advanced stages and present frequent alterations in cell cycle, hedgehog, beta-catenin and TGF-beta pathways, which may drive the immune depletion. These results may be exploited to develop novel combinatorial targeting strategies involving immunotherapies.

bioinformatics↗

bioRxiv2017

The whole-genome panorama of cancer drivers

The advance of personalized cancer medicine requires the accurate identification of the mutations driving each patients tumor. However, to date, we have only been able to obtain partial insights into the contribution of genomic events to tumor development. Here, we design a comprehensive approach to identify the driver mutations in each patients tumor and obtain a whole-genome panorama of driver events across more than 2,500 tumors from 37 types of cancer. This panorama includes coding and non-coding point mutations, copy number alterations and other genomic rearrangements of somatic origin, and potentially predisposing germline variants. We demonstrate that genomic events are at the root of virtually all tumors, with each carrying on average 4.6 driver events. Most individual tumors harbor a unique combination of drivers, and we uncover the most frequent co-occurring driver events. Half of all cancer genes are affected by several types of driver mutations. In summary, the panorama described here provides answers to fundamental questions in cancer genomics and bridges the gap between cancer genomics and personalized cancer medicine.

cancer biology↗