Analysis of promoter methylation in long-read sequenced advanced cancer patients | LC 25

Biography

Veronika Csizmok received her PhD degree in structural biology in 2006 with Dr Peter Tompa from the Institute of Enzymology (Budapest, Hungary). In 2007, she worked as a Marie Curie fellow with Dr Lucia Banci at the Magnetic Resonance Centre in Florence, Italy. After her postdoctoral work with Dr Julie Forman-Kay at SickKids, Toronto, she was a visiting scientist at Linköping University in Sweden. She is currently a Staff Scientist in the Clinical Informatics group at Genome Sciences Centre.

Abstract

Tumour samples (n=207; 65 with matched normal tissue) of 26 different cancer types from the Personalized OncoGenomics (POG) program were profiled on the Oxford Nanopore Technologies PromethION device, with DNA methylation and allele-specific methylation data collected. We define allelic differential methylation (aDM) as methylation specific to one of the alleles and hemizygous aberrant methylation (hAM) as abnormal methylation observed on one allele while the other allele is lost. In our cohort, we found 1,741 genes that show either aDM or hAM in at least one tumour sample, 75 of which are known tumour suppressor genes. Frequent promoter methylation was detected affecting genes involved in Wnt signaling (APC, SFRP1, SFRP2), homologous recombination repair (BRCA1, RAD51C, WRN), and transcriptional repression (MGA). Analysis of responses to platinum therapies or PARP inhibitors in cases with BRCA1 and RAD51C promoter methylation revealed positive clinical responses (partial response or stable disease) to platinum therapy. Small subclonal indels (8–27 bp) were detected in BRCA1 (n=2) or RAD51C (n=1) hypermethylated promoters, present only on reads that were not methylated, suggesting an emerging subclone with loss of methylation that may be resistant to platinum treatment. In an homologous recombination deficiency (HRD) patient with no known drivers, loss of methylation upstream of the hypomethylated RAD51C promoter was detected, resulting in the expression of non-canonical and truncated, non-functional RAD51C isoforms, which we subsequently confirmed by both short-read and long-read RNA sequencing data. This research demonstrates the utility of long-read sequencing in uncovering novel therapeutic targets and/or resistance mechanisms in the field of precision medicine.