Scarcity of Recurrent Regulatory Driver Mutations in Colorectal Cancer Revealed by Targeted Deep Sequencing

JNCI Cancer Spectrum
Rebecca C PoulosJason W H Wong

Abstract

Genetic testing of cancer samples primarily focuses on protein-coding regions, despite most mutations arising in noncoding DNA. Noncoding mutations can be pathogenic if they disrupt gene regulation, but the benefits of assessing promoter mutations in driver genes by panel testing has not yet been established. This is especially the case in colorectal cancer, for which few putative driver variants at regulatory elements have been reported. We designed a unique target capture sequencing panel of 39 colorectal cancer driver genes and their promoters, together with more than 35 megabases of regulatory elements focusing on gene promoters. Using this panel, we sequenced 95 colorectal cancer and matched normal samples at high depth, averaging 170× and 82× coverage, respectively. Our target capture sequencing design enabled improved coverage and variant detection across captured regions. We found cases with hereditary defects in mismatch and base excision repair due to deleterious germline coding variants, and we identified mutational spectra consistent with these repair deficiencies. Focusing on gene promoters and other regulatory regions, we found little evidence for base or region-specific recurrence of functional somatic mutations....Continue Reading

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Datasets Mentioned

BETA
EGAD00001004582

Methods Mentioned

BETA
amplicon sequencing
Assay
ChIP-seq
immunoprecipitation

Software Mentioned

Strelka
ClinVar
Factorbook
PolyPhen
PROVEAN
FunSeq2
Lancet
SIFT
Geneious
OncodriveFML

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