Long-read sequencing of an advanced cancer cohort resolves rearrangements, unravels haplotypes, and reveals methylation landscapes

Kieran O’Neill; Erin Pleasance; Jeremy Fan; Vahid Akbari; Glenn Chang; Katherine Dixon; Veronika Csizmók; Signe MacLennan; Vanessa Porter; Andrew Galbraith; Cameron J. Grisdale; Luka Culibrk; John H. Dupuis; Richard Corbett; James Hopkins; Reanne Bowlby; Pawan K. Pandoh; Duane E. Smailus; Dean Cheng; Tina Tzee Ling Wong; Connor Frey; Yaoqing Shen; Eleanor Lewis; Luis F. Paulin; Fritz Joachim Sedlazeck; Jessica Nelson; Eric Chuah; Karen L. Mungall; Richard A. Moore; Robin Coope

doi:10.1016/j.xgen.2024.100674

Genetic & Genomic MedicineCell GenomicsOct 14, 2024

Peer-reviewed journal article

Long-read sequencing of an advanced cancer cohort resolves rearrangements, unravels haplotypes, and reveals methylation landscapes

Kieran O’Neill iD, Erin Pleasance iD, Jeremy Fan, Vahid Akbari iD, Glenn Chang iD, Katherine Dixon iD, Veronika Csizmók, Signe MacLennan iD, Vanessa Porter iD, Andrew Galbraith, Cameron J. Grisdale iD, Luka Culibrk iD, John H. Dupuis iD, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan K. Pandoh iD, Duane E. Smailus iD, Dean Cheng, Tina Tzee Ling Wong iD, Connor Frey iD, Yaoqing Shen iD, Eleanor Lewis, Luis F. Paulin iD, Fritz Joachim Sedlazeck iD, , Steven J.M. Jones iD

Abstract

The Long-read POG dataset comprises a cohort of 189 patient tumours and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the Personalized Oncogenomics (POG) program and the Marathon of Hope Cancer Centres Network includes accompanying DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing of variants facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can be directly observed in Lynch syndrome. Promoter methylation in BRCA1 and RAD51C is a likely driver behind patterns of homologous recombination deficiency where no driver mutation was found. This dataset demonstrates applications for long-read sequencing in precision medicine, and is available as a resource for developing analytical approaches using this technology.

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