Abstract
BackgroundClinical-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.MethodsPatients 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.ResultsFifty-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.ConclusionsClinical 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.
Highlights
Clinical-grade whole-genome sequencing 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 (CRC) is typically initiated by a mutation in the Wnt signalling pathway gene APC [2] or associated genes (CTTNB1, RNF143, RSPO2/3) that lead to the formation of a polyp [3] that progresses via mutations in a number of oncogenes and tumour suppressors into an invasive cancer
Five patients presented with metastatic disease, and 18 patients had “high-risk” disease consisting of any of poor differentiation (4 patients), extra-mural vascular invasion (18 patients) or threatened circumferential resection margin (2 patients)
Summary
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. The Cancer Genome Atlas (TCGA) project set out to characterise mutations in colorectal cancer by exome sequencing of a cohort of 600 patients using the Agilent SureSelect panel via tumour-normal subtraction [5]. It confirmed recurrent mutations in APC, TP53, SMAD4, PIK3CA and KRAS as well as identifying recurrent mutations in ARID1A, SOX9 and AMER1 (FAM123B). Whether by the amplicon or hybridisation approach, may miss key oncogenic drivers due to allelic dropout or the biases inherent to targeting approaches [7], and the alterations seen in the publications resulting from these datasets may miss key insights that would be seen in a more expansive technology such as wholegenome sequencing
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
