Defining the Heterogeneity of Unbalanced Structural Variation Underlying Breast Cancer Susceptibility by Nanopore Genome Sequencing

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2023 Feb 16

PMID 36797466

Authors

Katherine Dixon

Yaoqing Shen

Kieran ONeill

Karen L Mungall

Simon Chan

Steve Bilobram

Wei Zhang

Marjorie Bezeau

Alshanee Sharma

Alexandra Fok

Andrew J Mungall

Richard Moore

Ian Bosdet

My Linh Thibodeau

Sophie Sun

Stephen Yip

Kasmintan A Schrader

Steven J M Jones

Affiliations

Soon will be listed here.

Abstract

Germline structural variants (SVs) are challenging to resolve by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at cancer susceptibility loci has not been reported. Nanopore long-read genome sequencing was performed for nineteen individuals with pathogenic copy number alterations in BRCA1, BRCA2, CHEK2 and PALB2 identified by prior clinical testing. Fourteen variants, which spanned single exons to whole genes and included a tandem duplication, were accurately represented. Defining the precise breakpoints of SVs in BRCA1 and CHEK2 revealed unforeseen allelic heterogeneity and informed the mechanisms underlying the formation of recurrent deletions. Integrating read-based and statistical phasing further helped define extended haplotypes associated with founder alleles. Long-read sequencing is a sensitive method for characterizing private, recurrent and founder SVs underlying breast cancer susceptibility. Our findings demonstrate the potential for nanopore sequencing as a powerful genetic testing assay in the hereditary cancer setting.

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