A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Miguel Cordova-DelgadoMaría Loreto BravoElisa CumsilleCharlotte N. HillMatías Muñoz-MedelMauricio P. PintoIgnacio N. RetamalMaría A. LavanderosJuan Francisco MiquelMaria Rodriguez-FernandezYuwei LiaoZhiguang LiAlejandro H. CorvalánARMISEN YAÑEZ, RICARDO AMADORICARDO AMADOARMISEN YAÑEZMarcelo GarridoLuis A. QuiñonesGareth I. Owen2023-06-072023-06-072021http://hdl.handle.net/11447/4655https://investigadores.udd.cl/handle/123456789/641610.1186/s12885-021-08745-02-s2.0-85115079952WOS:000696229400001Abstract Background Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life. predictive modelssingle nucleotide polymorphismchemotherapy toxicityfluoropyrimidinesplatinumsagedantineoplastic combined chemotherapy protocolscapecitabinecase-control studiesconfidence intervalsdihydrouracil dehydrogenase (nadp)dna-binding proteinsendonucleasesfemalefluorouracilgene frequencygenes, p53genotypeglutathione s-transferase piglycine hydroxymethyltransferasehumansleucovorinlogistic modelsmalemethylenetetrahydrofolate reductase (nadph2)middle agedmultidrug resistance-associated proteinsmultienzyme complexesnomogramsodds ratioorganoplatinum compoundsorotate phosphoribosyltransferaseorotidine-5'-phosphate decarboxylaseplatinum compoundspolymorphism, single nucleotidepyrimidinesquality of liferetrospective studiesstomach neoplasmsxeroderma pigmentosum group d proteincapecitabinecisplatindocetaxelfluoropyrimidinefluorouracilfolinic acidoxaliplatinplatinumantineoplastic agentcapecitabinedihydropyrimidine dehydrogenasedna binding proteinendonucleaseercc1 protein, humanercc2 protein, humanfluorouracilfolinic acidglutathione transferase p1glycine hydroxymethyltransferasegstp1 protein, humanmethylenetetrahydrofolate reductase (nadph2)mthfr protein, humanmultidrug resistance associated proteinmultidrug resistance-associated protein 2multienzyme complexorotate phosphoribosyltransferaseorotidine 5' phosphate decarboxylaseplatinum complexplatinum derivativepyrimidinepyrimidine derivativeshmt protein, humanuridine 5'-monophosphate synthasexeroderma pigmentosum group d proteinadultalgorithmallelearticleartificial neural networkcancer chemotherapycancer combination chemotherapycancer patientcase control studychronic liver diseaseclassification algorithmcontrolled studydiabetes mellitusdna extractiondrug combinationfemalegenegenotypeheart diseasehumanlogistic regression analysismalenauseaneurotoxicitynomogramoverall survivalpharmacogeneticsquality of liferetrospective studyrisk assessmentsingle nucleotide polymorphismstomach cancerthrombocytopeniavomitingagedconfidence intervalgene frequencygeneticsmiddle agedodds ratiopathologystatistical modelstomach tumortumor suppressor geneA case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancerResource Types::text::journal::journal article