Clinical-grade whole-genome sequencing and 3' transcriptome analysis of colorectal cancer patients.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ therapeutic use
Cluster Analysis
Colorectal Neoplasms
/ drug therapy
DNA Copy Number Variations
/ genetics
Databases, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Germ-Line Mutation
/ genetics
Humans
Male
Middle Aged
Mutation
/ genetics
Oncogenes
Phenotype
RNA-Seq
Telomere
/ genetics
Whole Genome Sequencing
Chemoradiotherapy
Genomics
Pathological complete response
Rectal cancer
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
25 02 2021
25 02 2021
Historique:
received:
29
04
2020
accepted:
11
02
2021
entrez:
26
2
2021
pubmed:
27
2
2021
medline:
21
1
2022
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33632293
doi: 10.1186/s13073-021-00852-8
pii: 10.1186/s13073-021-00852-8
pmc: PMC7908713
doi:
Substances chimiques
Antineoplastic Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
33Subventions
Organisme : Cancer Research UK
ID : C31641/A23923
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102732/Z/13/Z
Pays : United Kingdom
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