Clinical-grade whole genome sequencing of colorectal cancer and 3’ transcriptome analysis demonstrate targetable alterations in the majority of patients

Introduction Clinical grade whole genome sequencing (cWGS) has the potential to become 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 mutational signatures and tumour biology were gained by the use of 3’ RNAseq. 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 20% 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 identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies. ### Competing Interest Statement AB has received travel costs and honoraria from Illumina Inc., Oxford Nanopore, Ono Pharm and Bristol Myers Squibb. MH, MV, ZK, JB, MR are employees of Illumina, a public company that develops and markets systems for genetic analysis. ### Funding Statement This study was supported by grants from the Academy of Medical Sciences (ref 102732/Z/13/Z) and the Wellcome Trust (ref 102732/Z/13/Z). ADB is currently supported by a Cancer Research UK Advanced Clinician Scientist award (ref C31641/A23923) ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data will be made available on acceptance of the manuscript on EGA