Biology subjects

Nowinski, S.

Publications and source records attributed to Nowinski, S..

3 recordsLinked to original sources

bioRxiv2024

Long deletion signatures in repetitive genomic regions track somatic evolution and enable sensitive detection of microsatellite instability

Deficiency in the mismatch repair system (MMRd) causes microsatellite instability (MSI) in cancers and determines eligibility for immunotherapy. Here, we show that MMRd tumours harbour long-deletion signatures ([≥]2-5+ base pairs deleted in repetitive regions), which provide new insights into MSI evolution and enable sensitive MSI detection particularly in challenging clinical samples. Long deletions, accumulated through stepwise DNA slippage errors, are significantly more prevalent in metastatic MMRd tumours compared to primary tumours. Importantly, we show that long-deletion signatures harbour features that are distinct from background noise, making them robustly detectable even in shallow whole genome sequencing (sWGS, [~]0.1X coverage) of formalin-fixed samples. We constructed a machine learning classifier that uses these distinct features to detect Microsatellite Instability in LOw-quality (MILO) samples. MILO achieved 100% accuracy in detecting MSI in sWGS data with only 2%-15% tumour purity and demonstrated promise in identifying MMRd clones in precancerous intestinal lesions. We propose that MILO could be clinically used for the sensitive monitoring of MMRd cancer evolution from early to late stages, using minimal sequencing data from both archival and fresh-frozen samples with low tumour content. SignificanceMutational signatures characterised by long deletions in repetitive genomic regions provide a sensitive route to detect and track MMRd clone evolution, even with low purity shallow whole genome sequencing data.

bioinformatics↗

bioRxiv2023

The histone lysine demethylase KDM5C fine-tunes gene expression to regulate dendritic cell heterogeneity and function

The functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses that are essential for providing host protection. We found that KDM5C, a histone lysine demethylase of the KDM5 family regulates several aspects of conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Using mice conditionally deficient in KDM5C in DCs, we found that loss of KDM5C results in an increase in Ly6C- pDCs compared to Ly6C+ pDCs. We found that Ly6C- pDCs, compared to Ly6C+ pDCs, have increased expression of cell cycle genes, decreased expression of activation markers and limited ability to produce type I interferon (IFN). Both KDM5C-deficient Ly6C- and Ly6C+ pDCs have increased expression of activation markers, however, are dysfunctional and have limited ability to produce type I IFN. For conventional cDCs, KDM5C deficiency resulted in increased proportions of cDC2Bs (CLEC12A+, ESAM-) and cDC1s, which was partly dependent on type I IFN and pDCs. Using ATAC-seq, RNA-seq, and CUT&RUN for histone marks, we found that KDM5C regulates epigenetic programming of cDC1. In the absence of KDM5C, we found an increased expression of inflammatory markers, consistent with our previous results in bone marrow-derived DCs. However, we also found a decrease in mitochondrial metabolism genes and altered expression of cDC lineage-specific genes. In response to Listeria infection, KDM5C-conditionally deficient mice mounted reduced CD8+ T cell responses, indicating that KDM5C expression in DCs is necessary for their function. Thus, KDM5C is a key regulator of DC heterogeneity by modulating the balance of DC subsets and serves as a critical driver of the epigenetic programming and functional properties of DCs.

immunology↗

bioRxiv2020

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, the loss and gain of whole and part chromosomes, is near-ubiquitous in cancer genomes and likely defines cancer cell biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterised. Here we perform longitudinal genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that represent distinct stages of tumour evolution through metastasis and treatment. Adenomas typically had few copy number alterations (CNAs) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual CRC glands from the same tumour typically had very similar karyotypes, despite evidence of ongoing instability at the cell level in patient tumours, cell lines and organoids. CNAs in metastatic lesions sampled from liver and other organs, after chemotherapy or targeted therapies, and in late recurrences were typically similar to the primary tumour. Mathematical modelling and statistical inference indicated that these data are consistent with the action of negative selection on CNAs that traps cancer cell genomes on a fitness peak defined by the specific pattern of chromosomal aberrations. These data suggest that the initial progression of colorectal cancer requires the traversal of a rugged fitness landscape and subsequent CNA evolution, including metastatic dissemination and therapeutic resistance, is constrained by negative selection.

cancer biology↗