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Abstract
Background Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients.
Methods A case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing −log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation.
Results Glycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 (HAX1) and hyaluronan-mediatedmotility receptor (HMMR), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis.
Conclusions Combining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC.
- Gastroenterology
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genetic Variation
- Gene Expression
Data availability statement
Data are available upon reasonable request. Supplementary data are attached in additional files. The other datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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- Gastroenterology
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genetic Variation
- Gene Expression
Data availability statement
Data are available upon reasonable request. Supplementary data are attached in additional files. The other datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Footnotes
Contributors Conceptualisation: IT and PYC. Data curation: LFT, MW and ML. Formal analysis: LFT, FG and PYC. Funding acquisition: PYC. Investigation: LFT, MW and ML. Methodology: LFT and PYC. Project administration: LFT, ML and PYC. Resources: IT, EW, ET and CLT. Supervision: PYC. Validation: LFT, MW and ML. Writing—original draft: PYC. Writing—review and editing: LFT and PYC; guarantor: PYC.
Funding This research was funded by in part by a Singapore National Medical Research Council grant (NMRC/OFIRG/0004/2016) to PYC.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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