Biology subjects

Whitehall, V.

Publications and source records attributed to Whitehall, V..

3 recordsLinked to original sources

bioRxiv2024

Unraveling lncRNA Diversity at a Single Cell Resolution and in a Spatial Context across Different Cancer Types

Long non-coding RNAs (lncRNAs) play pivotal roles in gene regulation and disease, including cancer. Overcoming the limitations of lncRNA analysis with bulk data, we analyzed single-cell and spatial transcriptomics data to uncover 354937 novel lncRNAs and their functions across 13 cancer types. LncRNA functions were assessed by identifying their cell-type specificity and distinct spatial distributions across different tissue regions. First, lncRNAs were computationally validated by comparing to existing databases, and experimentally validated using spatial long read sequencing methods. Further, genome-wide computation of spatial-autocorrelation identified coexpression of lncRNAs with cancer-associated protein coding genes across the tissue. Additionally, genomic co-localization of lncRNAs with regulatory features and disease-associated genetic variants suggest possible functional association. The identified lncRNAs were analyzed for responses to immunotherapy and prognostic value, revealing cancer-outcome associated lncRNAs. We have made this novel resource available as an open website SPanC-Lnc hosted on AWS cloud to serve as a pan-cancer atlas of single cell- and spatially-resolved lncRNAs. These can complement established biomarkers because they reflect the unique characteristics of specific cell populations within tumors, offering new insights into disease progression and treatment response.

cancer biology↗

bioRxiv2020

APC Mutation marks an aggressive subtype of BRAF mutant colorectal cancers that are associated with early-onset and dismal prognosis

Background & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2x10-5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8x10-21) compared to animals with Apc or Braf mutation alone. ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

cancer biology↗

bioRxiv2018

Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer

BACKGROUNDColorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.\n\nRESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation of BRAF (74%, P<0.0001) or KRAS (55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.\n\nCONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.

genomics↗