Abstract
Metabolic alterations encountered in tumors are well recognized and considered as a hallmark of cancer. In addition to Warburg Effect, epidemiological and experimental studies support the crucial role of lipid metabolism in colorectal cancer (CRC). The overexpression of four lipid metabolism-related genes (ABCA1, ACSL1, AGPAT1 and SCD genes) has been proposed as prognostic marker of stage II CRC (ColoLipidGene signature).In order to explore in depth the transcriptomic and genomic scenarios of ABCA1, ACSL1, AGPAT1 and SCD genes, we performed a transcriptomic meta-analysis in more than one thousand CRC individuals. Additionally we analyzed their genomic coding sequence in 95 patients, to find variants that could orchestrate CRC prognosis.We found that genetic variant rs3071, located on SCD gene, defines a 9.77% of stage II CRC patients with high risk of death. Moreover, individuals with upregulation of ABCA1 and AGPAT1 expression have an increased risk of CRC recurrence, independently of tumor stage.ABCA1 emerges as one of the main contributors to signature’s prognostic effect. Indeed, both high ABCA1 expression and presence of tumoral genetic variants located in ABCA1 coding region, seem to be associated with CRC risk of death. In addition the non-synonymous polymorphism rs2230808, located on ABCA1, is associated with gene expression. Patients carrying at least one copy of minor allele showed higher levels of ABCA1 expression than patients carrying homozygous major allele.This study broaden the prognostic value of ABCA1, ACSL1, AGPAT1 and SCD genes, independently of CRC tumor stage, leading to future precision medicine approaches and “omics”-guided therapies.
Highlights
Colorectal cancer (CRC) is a heterogeneous disease that relevantly contributes to cancer mortality and morbidity
In order to test the prognostic value of ColoLipidGenes for patients with CRC tumors, we performed a meta-analysis based on publicly available transcriptomic data
We investigated whether the individual gene expression of ATP-Binding Cassette Subfamily-A Member 1 (ABCA1), Acyl-CoA Synthetase 1 (ACSL1), 1-Acylglycerol-3-Phosphate O-Acyltransferase 1 (AGPAT1) and Stearoyl-CoAdesaturase 1 (SCD), was associated with recurrence in a large series of CRC patients of stages from I to III, using gene expression datasets from Gene Expression Omnibus (GEO) repository database
Summary
Colorectal cancer (CRC) is a heterogeneous disease that relevantly contributes to cancer mortality and morbidity. Many efforts have been performed by the scientific community, in order to find CRC expression patterns that allow us an accurate disease stratification into different prognostic subgroups and/or in connection with response to therapies. Nextgeneration sequencing (NGS) technologies have been contributing to a better understanding of the CRC development. Four transcriptomic consensus molecular subtypes (CMS) of CRC were defined: CMS1 or microsatellite instability (MSI) immune subtype, CMS2 or canonical, CMS3 or metabolic and CMS4 or mesenchymal subtype. Metabolic subtype tumors, CMS3, have been characterized as those which harbor KRAS mutations, a mixed MSI status, low somatic copy number alterations (SCNA) and low CpG island methylator phenotype (CIMP). CMS3 tumors exhibit a prominent metabolic activation with a clear enrichment for multiple metabolism signatures, in connection with the presence of KRAS-activating mutations that have been described as inducing metabolic reprogramming [5]
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