Biology subjects

Sherwood, K.

Publications and source records attributed to Sherwood, K..

6 recordsLinked to original sources

bioRxiv2026

Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival

Pleural mesothelioma (PM) is a tumour type showing high structural complexity but the full spectrum of variants present and their impacts are poorly understood. We comprehensively describe the mutational landscape of mesothelioma, exploiting a large (N=443) cohort profiling the tumour genome and transcriptome in parallel. We find that the majority of candidate driver variants are mediated by copy number alterations (CNAs) and discover high frequencies of complex rearrangements across most tumours, dominated by chromothripsis (74% of tumours) and chromoplexy (59%). Chromothripsis contributes to significant CNA hotspots to delete known PM tumour suppressor genes such as CDKN2A, NF2 and BAP1, thought to be among the earliest events in PM development; and the presence of chromothripsis is associated with significantly worse patient survival. We also discover multi-faceted crosstalk between the mitochondrial and nuclear genomes during PM evolution, involving alterations to both genomes, and mitochondrial expression changes associated with subtypes and chromothripsis.

cancer biology↗

bioRxiv2026

BatchVaria: a variance-aware framework for evaluating batch correction in high-dimensional omics data

SummaryBatch effects and other unwanted technical sources of variation remain a persistent challenge in the integrative analysis of high-dimensional-omics data. Although established methods such as ComBat effectively mitigate batch-associated signal, their impact on biologically meaningful variation is frequently evaluated in an ad hoc and non-quantitative manner. This is particularly problematic in heterogeneous disease contexts, such as breast cancer transcriptomics, where technical and biological sources of variation may be partially confounded. We present BatchVaria, an R package that implements a variance-aware framework for batch correction and post-adjustment evaluation. BatchVaria integrates variance component modelling, batch adjustment, and systematic re-profiling within a unified analysis container, enabling iterative quantification and reassessment of technical and biological variance contributions while preserving analytical provenance. By supporting multiple variance profiling engines and structured storage of intermediate results, BatchVaria facilitates transparent and reproducible evaluation of batch correction strategies. We demonstrate the utility of BatchVaria using a publicly available breast cancer transcriptomic dataset with known covariate-driven structure, illustrating how iterative variance profiling can guide responsible batch correction without erosion of subtype-associated biological signal.

bioinformatics↗

bioRxiv2026

DNA methylation signatures of mismatch repair-deficient colorectal cancer

BackgroundColorectal cancer (CRC) is a molecularly heterogeneous disease shaped by both genetic and epigenetic alterations. Approximately 15% of CRCs display widespread CpG island hypermethylation, known as the CpG Island Methylator Phenotype (CIMP). CIMP-high (CIMP-H) tumours frequently exhibit MLH1 promoter hypermethylation, leading to mismatch repair deficiency (MMRd) and microsatellite instability (MSI). However, DNA methylation patterns associated with MSI, independent of CIMP and MLH1 silencing, and the influence of clinical variables such as anatomical location and patient age on the CRC methylome remain poorly characterised. MethodsWe performed epigenome-wide DNA methylation profiling of 259 primary CRC tissue samples using the Illumina EPICv2 array, comparing differential methylation between MSI and microsatellite stable (MSS) CRC, adjusting for tumour purity, MLH1 promoter methylation, CIMP status, and anatomical location, to account for known confounders. We further evaluated the independent effects of anatomical location and patient age on global methylation patterns. ResultsEpigenome-wide differential methylation between MSS and MSI CRC was dominated by MLH1 promoter hypermethylation. After adjusting for MLH1 hypermethylation and CIMP status, we identified a distinct set of 656 CpG sites associated with MMRd independent of MLH1 silencing. These included hypermethylation at LRP6, GSK3{beta}, and CDK12, implicating altered WNT signalling and transcriptional regulation pathways. Comparison of MSI subgroups revealed the co-occurrence of MLH1 hypermethylation with promoter hypermethylation at TXNRD1. Anatomical location showed a strong independent effect on methylation patterns, while we observed only modest effects of patient age on the CRC methylome after adjustment for confounders. ConclusionsWe identified a distinct methylation profile distinguishing MSS and MSI CRC, including MLH1-independent markers of MMRd, as well as novel differentially methylated loci within MSI subgroups. We further showed that anatomical location has a strong independent impact on the CRC methylome. Together, these findings refine the molecular characterisation of CRC and highlight potential epigenetic markers that could inform patient stratification and precision oncology.

cancer biology↗

bioRxiv2024

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

cancer biology↗

bioRxiv2022

Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions

To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-{beta}/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions of PIK3R1 and PWRN1, as well as amplification of CCND3 and NEDD9. Putative driver structural variants included BRD4 and SOX9 regulatory elements, and ACVR2A and ANKRD11 hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenic E. coli signature and TP53 mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.

genomics↗

bioRxiv2021

Germline loss-of-function variants in the base-excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and -uniquely amongst CRC predisposition syndromes- to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AML.

genetics↗