Long-Read Sequencing of an Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, and Reveals Methylation Landscapes

Authors

Kieran O'Neill
Erin Pleasance
Jeremy Fan
Vahid Akbari
Glenn Chang
Katherine Dixon
Veronika Csizmok
Signe MacLennan
Vanessa Porter
Andrew Galbraith
Cameron J Grisdale
Luka Culibrk
John H Dupuis
Richard Corbett
James Hopkins
Reanne Bowlby
Pawan Pandoh
Duane E Smailus
Dean Cheng
Tina Wong
Connor Frey
Yaoqing Shen
Eleanor Lewis
Luis F Paulin
Fritz J Sedlazeck
Jessica M T Nelson
Eric Chuah
Karen L Mungall
Richard A Moore
Robin Coope
Andrew J Mungall
Melissa K McConechy
Laura M Williamson
Kasmintan A Schrader
Stephen Yip
Marco A Marra
Janessa Laskin
Steven J M Jones

Publication Date

11-13-2024

Journal

Cell Genomics

DOI

10.1016/j.xgen.2024.100674

PMID

39406235

PMCID

PMC11605692

PubMedCentral® Posted Date

10-14-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, DNA Methylation, Haplotypes, Neoplasms, Cohort Studies, Gene Rearrangement, Sequence Analysis, DNA, Promoter Regions, Genetic, High-Throughput Nucleotide Sequencing, MutL Protein Homolog 1, cancer genomics, nanopore long-read sequencing, structural variant detection, allelically differentially methylated regions (aDMRs), allele-specific expression, long-range phasing, homologous recombination deficiency, extrachromosomal DNA, personalized medicine, TFRI MOHCCN

Abstract

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes 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 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 homologous recombination deficiency where no coding 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.