title: Variant alleles in factor V, prothrombin, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase and risk of thromboembolism in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab.
abstract: Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (χ2test P>0.20). FVL G1691A and PT G20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFR C677T in homozygosis in 29 (16.2%), MTHFR A1298C in homozygosis in 13 (7.3%); PAI-1 5G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVL G1691A and PT G20210A as well as MTHFR C677T and PAI-1 4G allele were significantly associated, whereas MTHFR A1298C was not. At multivariable model including PT G20210A, MTHFR C677T and PAI-1 4G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan, Italy.
authors.forename: F S
authors.initials: FS
authors.lastname: Falvella
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Miceli
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nichetti
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cheli
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Infante
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Martinetti
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Marmorino
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sottotetti
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Caporale
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco, Italy.|Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital "Luigi Sacco", Università di Milano, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pietrantonio
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000068258:Bevacizumab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005165:Factor V / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011516:Prothrombin / Q000235:genetics*; D012306:Risk; D013923:Thromboembolism / Q000235:genetics*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D000068258:Bevacizumab; D005165:Factor V; D011516:Prothrombin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)