Biology subjects

Grimmond, S.

Publications and source records attributed to Grimmond, S..

3 recordsLinked to original sources

bioRxiv2026

Genomic alterations enable BRCA1 methylation loss and promoter bypass to drive resistance in high-grade serous ovarian cancer

BRCA1 promoter methylation predicts sensitivity to PARP inhibitors in high-grade serous ovarian cancer, yet therapeutic resistance is common and mechanistically unresolved. Using long-read direct DNA sequencing of patient-derived xenografts and cell lines, we resolved BRCA1 methylation at single-molecule resolution with structural and transcriptomic analyses. We revealed two convergent PARP inhibitor and platinum resistance mechanisms, validated in patient tumors. First, focal, allele-specific loss of BRCA1 methylation arose through local cis-acting genomic alterations, instead of global epigenetic reprogramming. Engineered in cis sequence alterations near the methylated BRCA1 promoter were sufficient to induce methylation loss, restore homologous recombination, and confer resistance. Similar associations were observed across the genome, suggesting this mechanism extends beyond BRCA1. Second, BRCA1 expression was restored despite intact promoter methylation via structural variant-mediated promoter bypass or alternative transcription initiation. Together, these findings redefine BRCA1 methylation loss as a locus-restricted process and reveal multiple routes by which tumors escape PARP inhibitor therapy. Statement of SignificanceWe show that high-grade serous ovarian cancers can restore BRCA1 expression after therapy through multiple genomic mechanisms, including local methylation loss and promoter bypass, thereby re-establishing homologous recombination and driving PARP inhibitor resistance. These findings challenge reliance on BRCA1 methylation alone as a predictive biomarker and support rational combination therapies for more durable responses.

cancer biology↗

bioRxiv2018

Platypus Induced Pluripotent Stem Cells: the Unique Pluripotency Signature of a Monotreme

Summary StatementThe generation and transcriptome analysis of the first induced pluripotent stem cells from the platypus reveals SOX2 has been a key driver of the expanded pluripotency regulatory network in placental mammals.\n\nABSTRACTThe mechanisms by which pluripotency has evolved remain unclear. To gain insight into the evolution of mammalian pluripotency we have generated induced pluripotent stem cells (piPSCs) from the platypus. Deep sequencing of the piPSC transcriptome revealed that piPSCs robustly express the core eutherian pluripotency factors OCT4, SOX2 and NANOG. Given the more extensive role of SOX3 over SOX2 in avian pluripotency, our data indicate that between 315 million years and 166 million years ago primitive mammals replaced the role of SOX3 in the vertebrate pluripotency network with SOX2. DAX1/NR0B1 is not expressed in piPSCs and an analysis of the platypus DAX1 promoter revealed the absence of a proximal SOX2-binding DNA motif known to be critical for DAX1 expression in eutherian pluripotent stem cells, suggesting that the acquisition of SOX2 responsiveness by DAX1 has facilitated its recruitment into the pluripotency network of eutherians. We further show that the expression ratio of X chromosomes to autosomes (X1-5 X1-5:AA) is approximately equal to 1 indicating that there is no upregulation of X-linked genes and that there is no preference for silencing of maternal or paternal alleles (ie imprinting).

cell biology↗

bioRxiv2017

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern - these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of [≥]1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.

cancer biology↗