Biology subjects

Katainen, R.

Publications and source records attributed to Katainen, R..

4 recordsLinked to original sources

bioRxiv2019

Colibactin DNA damage signature indicates causative role in colorectal cancer

Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks+ E.coli. Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential. This corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the identified motifs in colorectal cancers. Our work provides direct evidence for a role of colibactin in the etiology of human cancer.\n\nOne sentence summaryWe identify a mutational signature of colibactin, which is significantly enriched in human colorectal cancers.

microbiology↗

bioRxiv2019

Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity and yet, how these POLE mutants generate mutations across cancer genomes and influence driver events remains poorly understood. Here we analyzed 7,345 colorectal cancer samples, including nine whole genome sequenced samples harboring POLE mutations. Our analysis identified differential mutation spectra across the mutants including methylation-independent enrichment of C>T mutations in POLE V411L. In contrast, analysis of other genomic regions showed similar mutation profiles across the different POLE mutants. Notably, we found that POLE mutants with the TP53 R213* mutation, caused by a TT[C>T]GA substitution, have significantly higher relative frequency of this mutational context compared with samples without this mutation. This finding demonstrates that variations in underlying mutation spectra can increase the likelihood of specific driver mutation formation.

genomics↗

bioRxiv2018

Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We found highly variable retrotransposon activity among tumors and identified recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identified insertions in APC, likely to be tumor-initiating events. Insertions were positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions was independently associated with poor disease-specific survival.

genomics↗

bioRxiv2017

BasePlayer: Versatile Analysis Software For Large-Scale Genomic Variant Discovery

Next-generation sequencing (NGS) is being routinely applied in life sciences and clinical practice, where the interpretation of the resulting massive data has become a critical challenge. Computational workflows, such as the Broad GATK, have been established to take raw sequencing data and produce processed data for downstream analyses. Consequently, results of these computationally demanding workflows, consisting of e.g. sequence alignment and variant calling, are increasingly being provided for customers by sequencing and bioinformatics facilities. However, downstream variant analysis, whole-genome level in particular, has been lacking a multi-purpose tool, which could take advantage of rapidly growing genomic information and integrate genetic variant, sequence, genomic annotation and regulatory (e.g. ENCODE) data interactively and in a visual fashion. Here we introduce a highly efficient and user-friendly software, BasePlayer (http://baseplayer.fi), for biological discovery in large-scale NGS data. BasePlayer enables tightly integrated comparative variant analysis and visualization of thousands of NGS data samples and millions of variants, with numerous applications in disease, regulatory and population genomics. Although BasePlayer has been designed primarily for whole-genome and exome sequencing data, it is well-suited to various study settings, diseases and organisms by supporting standard and upcoming file formats. BasePlayer transforms an ordinary desktop computer into a large-scale genomic research platform, enabling also a non-technical user to perform complex comparative variant analyses, population frequency filtering and genome level annotations under intuitive, scalable and highly-responsive user interface to facilitate everyday genetic research as well as the search of novel discoveries.

bioinformatics↗