Most large structural variants in cancer genomes can be detected without long reads.

TitleMost large structural variants in cancer genomes can be detected without long reads.
Publication TypeJournal Article
Year of Publication2023
AuthorsChoo Z-N, Behr JM, Deshpande A, Hadi K, Yao X, Tian H, Takai K, Zakusilo G, Rosiene J, Paula ADa Cruz, Weigelt B, Setton J, Riaz N, Powell SN, Busam K, Shoushtari AN, Ariyan C, Reis-Filho J, de Lange T, ImieliƄski M
JournalNat Genet
Volume55
Issue12
Pagination2139-2148
Date Published2023 Dec
ISSN1546-1718
KeywordsBreast Neoplasms, Chromosome Aberrations, Female, Genome, Human, Genomic Structural Variation, Genomics, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA
Abstract

Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.

DOI10.1038/s41588-023-01540-6
Alternate JournalNat Genet
PubMed ID37945902
PubMed Central IDPMC10703688
Grant ListR35 CA210036 / CA / NCI NIH HHS / United States
F31 CA232465 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
F30 CA268747 / CA / NCI NIH HHS / United States

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