Biology subjects

Tan, D. S. W.

Publications and source records attributed to Tan, D. S. W..

3 recordsLinked to original sources

bioRxiv2023

Dearth of smoking-induced mutations in oncogene-driven non-small-cell lung cancer despite smoking exposure

Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these "non-smoking-related oncogenes" (NSROs). In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers, and the clonal architecture and genomic landscape of these tumors remain unknown. We investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. NSRO-driven NSCLCs in smokers and non-smokers have similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle, suggesting that smoking still affects tumor phenotype independently of genomic alterations. Statement of significanceThis study highlights the lack of genomic scars caused by smoking in NSCLCs driven by non-smoking-related oncogenes regardless of smoking history. The impact of smoking on these tumors is mainly non-genomic. The transcriptomic features of NSCLCs associated with smoking may help in the development of therapeutic approaches.

cancer biology↗

bioRxiv2021

Obtaining Spatially Resolved Tumor Purity Maps Using Deep Multiple Instance Learning In A Pan-cancer Study

Tumor purity is the proportion of cancer cells in the tumor tissue. An accurate tumor purity estimation is crucial for accurate pathologic evaluation and for sample selection to minimize normal cell contamination in high throughput genomic analysis. We developed a novel deep multiple instance learning model predicting tumor purity from H&E stained digital histopathology slides. Our model successfully predicted tumor purity from slides of fresh-frozen sections in eight different TCGA cohorts and formalin-fixed paraffin-embedded sections in a local Singapore cohort. The predictions were highly consistent with genomic tumor purity values, which were inferred from genomic data and accepted as the golden standard. Besides, we obtained spatially resolved tumor purity maps and showed that tumor purity varies spatially within a sample. Our analyses on tumor purity maps also suggested that pathologists might have chosen high tumor content regions inside the slides during tumor purity estimation in the TCGA cohorts, which resulted in higher values than genomic tumor purity values. In short, our model can be utilized for high throughput sample selection for genomic analysis, which will help reduce pathologists workload and decrease inter-observer variability. Moreover, spatial tumor purity maps can help better understand the tumor microenvironment as a key determinant in tumor formation and therapeutic response.

cancer biology↗

bioRxiv2018

Mutational signature analysis of Asian OSCCs reveals novel mutational signature with exceptional sequence context specificity

Mutational signatures can reveal the history of mutagenic processes that cells were exposed to prior to and during tumourigenesis. We expect that as-yet-undiscovered mutational processes will shed further light on mutagenesis leading to carcinogenesis. With this in mind, we analyzed the mutational spectra of 36 Asian oral squamous cell carcinomas. The mutational spectra of two samples from patients who presented with oral bacterial infections, showed novel mutational signatures. One of these novel signatures, SBS_AnT, is characterized by a preponderance of thymine mutations, strong transcriptional strand bias, and striking enrichment for adenines in the 4 base pairs 5 of mutation sites. Examination of publicly available sequencing data revealed SBS_AnT in 25 tumours from several mucosal tissue types, all of which harbour human symbionts or are adjacent to tissues that harbour symbionts. Data in a preprint released while this manuscript was in revision strongly suggest that the bacterial compound colibactin causes SBS_AnT.

genomics↗