title: 3'UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients.
abstract: 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.
authors.affiliation: Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Vargas
authors.affiliation: Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.|Precision Oncology Laboratory (POL), Infanta Sofía University Hospital, San Sebastián de los Reyes, Madrid, Spain.|Translational Oncology Laboratory, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Moreno-Rubio
authors.affiliation: Biostatistics and Bioinformatics Unit, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Herranz
authors.affiliation: Translational Oncology Laboratory, La Paz University Hospital (IdiPAZ), Madrid, Spain.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America.
authors.forename: Paloma
authors.initials: P
authors.lastname: Cejas
authors.affiliation: Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Molina
authors.affiliation: Translational Oncology Laboratory, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Mendiola
authors.affiliation: Pathology Department, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Burgos
authors.affiliation: Medical Oncology, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Custodio
authors.affiliation: Translational Oncology Laboratory, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: De Miguel
authors.affiliation: Biostatistics and Bioinformatics Unit, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Martín-Hernández
authors.affiliation: Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Reglero
authors.affiliation: Medical Oncology, La Paz University Hospital (IdiPAZ), Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Feliu
authors.affiliation: Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ramírez de Molina
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003066:Coenzyme A Ligases / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D003066:Coenzyme A Ligases; C583414:ACSL1 protein, human