ColoLipidGene: Signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients

Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolismrelated genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk groupThis work was supported by Ministerio de Ciencia e Innovación del Gobierno de España (Plan Nacional I + D + i AGL2013–48943-C2–2-R and IPT-2011–1248-060000), Comunidad de Madrid (P2013/ABI-2728. ALIBIRDCM) and European Union Structural Funds. CIBEREHD is funded by the Instituto de Salud Carlos III. This is a collaborative study between the Molecular Oncology Unit of The Institute of Advanced Studies of Madrid IMDEA Food and the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD

3'UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients.

Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3'-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69-5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a "risk genotype" of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC

Clinical characteristics of stage II and III CC patients (n = 284).

<p>Clinical characteristics of stage II and III CC patients (n = 284).</p

Box plots of the association between gene expression level for <i>ACSL1</i> and genotype for rs8086 SNP located on the 3’-UTR region.

<p>The box plots show how the <i>ACSL1</i> expression values are distributed for each genotype from the Additive, Dominant and Recessive model of inheritance for <i>ACSL1</i> rs8086 SNP in stage II and III CC patients. The p-values were calculated using the non-parametric Krustal-Wallis and Mann-Whitney tests, respectively. The line within the box indicate the median of level expression. The gene expression data were normalized using the geometric mean of the internal control genes <i>GAPDH</i> and <i>B2M</i>.</p

Kaplan-Meier curve of <i>ACSL1</i> SNP rs8086 and <i>SCD</i> SNP rs522951 on DFS for stage II and III CC patients in a recessive and dominant model of inheritance, respectively.

<p>P-value was calculated by Log-rank test.</p

Association between <i>ACSL1</i> and <i>SCD</i> gene expression level and the different genotypes from the diverse models of inheritance for <i>ACSL1</i> rs8086 and <i>SCD</i> rs522951 SNPs in stage II and III CC patients.

<p>Association between <i>ACSL1</i> and <i>SCD</i> gene expression level and the different genotypes from the diverse models of inheritance for <i>ACSL1</i> rs8086 and <i>SCD</i> rs522951 SNPs in stage II and III CC patients.</p