Clinical-grade whole-genome sequencing and 3' transcriptome analysis of colorectal cancer patients
Stodolna, Agata He, Miao Vasipalli, Mahesh Kingsbury, Zoya Becq, Jennifer Stockton, Joanne D Dilworth, Mark P James, Jonathan Sillo, Toju Blakeway, Daniel
Stodolna, Agata
He, Miao
Vasipalli, Mahesh
Kingsbury, Zoya
Becq, Jennifer
Stockton, Joanne D
Dilworth, Mark P
James, Jonathan
Sillo, Toju
Blakeway, Daniel
Abstract
Background: Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3' transcriptome analysis would give new insights into colorectal cancer.
Methods: Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3' RNA-seq.
Results: Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy.
Conclusions: Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.
MIDER Authors
Affiliations
University of Birmingham; Illumina Cambridge; University Hospitals Birmingham NHS Foundation Trust
Date
2021-02-25
Type
Article
Collections
Citation
Stodolna A, He M, Vasipalli M, Kingsbury Z, Becq J, Stockton JD, Dilworth MP, James J, Sillo T, Blakeway D, Ward ST, Ismail T, Ross MT, Beggs AD. Clinical-grade whole-genome sequencing and 3' transcriptome analysis of colorectal cancer patients. Genome Med. 2021 Feb 25;13(1):33. doi: 10.1186/s13073-021-00852-8.