Biology subjects

Yang, S. Y. C.

Publications and source records attributed to Yang, S. Y. C..

3 recordsLinked to original sources

bioRxiv2022

Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours

To inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naive pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Excluded (17%). We validated these clusters using immunohistochemistry, methylation immune inference, and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune-cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

genomics↗

bioRxiv2021

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

Whole genome sequencing of primary breast tumors enabled the identification of cancer driver genes 1,2 and non-coding cancer driver plexuses from somatic mutations 3-6. However, differentiating driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform delivery of personalized cancer medicine. Herein, we reveal an enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of [~]100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors in luminal breast cancer, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

cancer biology↗

bioRxiv2018

Genome analysis and data sharing informs timing of molecular events in pancreatic neuroendocrine tumour

Neuroendocrine tumours (NETs) are rare, slow growing cancers that present in a diversity of tissues. To understand molecular underpinnings of gastrointestinal (GINET) and pancreatic NETs (PNETs), we profiled 45 tumours combining exome, RNA, and shallow whole genome sequencing, as well as fluorescent in situ hybridization. In addition to expected somatic mutations and copy number alterations, we found that PNETs contained a highly consistent copy neutral loss-of-heterozygosity (CN-LOH) profile affecting over half of the genome; a greater percentage than any cancer analyzed to date. Our data indicates that onset of extreme autozygosity may be progressive, associated with metastasis, and initially triggered by the loss of DAXX/ATRX, and subsequent biallelic loss of MEN1. We confirmed this molecular timing model using targeted clinical sequencing data from an additional 43 NETs made available by the AACR GENIE project. Against this background of CN-LOH, several chromosomal regions consistently retained heterozygosity, suggesting selection for crucial allele-specific components specific to PNET progression and potential new therapeutic targets.\n\nStatement of significanceWe have discovered that pancreatic neuroendocrine tumours contain a characteristic pattern of copy neutral loss-of-heterozygosity affecting the majority of the genome following mutations of MEN1 and ATRX/DAXX. Against this background of loss-of-heterozygosity, specific genomic regions are consistently retained and may therefore contain vulnerable therapeutic targets for pancreatic neuroendocrine tumours.

cancer biology↗