Clinical-grade whole-genome sequencing and 3' transcriptome analysis of colorectal cancer patients

Agata Stodolna, Miao He, Mahesh Vasipalli, Zoya Kingsbury, Jennifer Becq, Joanne D Stockton, Mark P Dilworth, Jonathan James, Toju Sillo, Daniel Blakeway, Stephen T Ward, Tariq Ismail, Mark T Ross, Andrew D Beggs

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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.

Original languageEnglish
Article number33
Number of pages15
JournalGenome medicine
Issue number1
Early online date25 Feb 2021
Publication statusPublished - Dec 2021


  • Chemoradiotherapy
  • Genomics
  • Pathological complete response
  • Rectal cancer


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