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

Felicia Stefania Falvella, C. Cremolini, R Miceli, F. Nichetti, Stefania Cheli, C. Antoniotti, G. Infante, A Martinetti, Federica Marmorino, E Sottotetti, R Berenato, M Caporale, A Colombo, F de Braud, M Di Bartolomeo, E Clementi, F Loupakis, F Pietrantonio

Research output: Contribution to journalArticle

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 (χ(2) test 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.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.22.

Original languageEnglish
JournalPharmacogenomics Journal
DOIs
Publication statusE-pub ahead of print - Mar 22 2016

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Methylenetetrahydrofolate Reductase (NADPH2)
Factor V
Plasminogen Activator Inhibitor 1
Thromboembolism
Prothrombin
Colorectal Neoplasms
Alleles
Drug Therapy
Single Nucleotide Polymorphism
Obesity
Genotype
Validation Studies
Pharmacogenetics
Platelet Count
Publications
Bevacizumab
Real-Time Polymerase Chain Reaction
DNA
Therapeutics
Neoplasms

Keywords

  • Journal Article

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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. / Falvella, Felicia Stefania; Cremolini, C.; Miceli, R; Nichetti, F.; Cheli, Stefania; Antoniotti, C.; Infante, G.; Martinetti, A; Marmorino, Federica; Sottotetti, E; Berenato, R; Caporale, M; Colombo, A; de Braud, F; Di Bartolomeo, M; Clementi, E; Loupakis, F; Pietrantonio, F.

In: Pharmacogenomics Journal, 22.03.2016.

Research output: Contribution to journalArticle

Falvella, Felicia Stefania ; Cremolini, C. ; Miceli, R ; Nichetti, F. ; Cheli, Stefania ; Antoniotti, C. ; Infante, G. ; Martinetti, A ; Marmorino, Federica ; Sottotetti, E ; Berenato, R ; Caporale, M ; Colombo, A ; de Braud, F ; Di Bartolomeo, M ; Clementi, E ; Loupakis, F ; Pietrantonio, F. / 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. In: Pharmacogenomics Journal. 2016.
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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 (χ(2) test 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.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.22.",
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T1 - 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

AU - Falvella, Felicia Stefania

AU - Cremolini, C.

AU - Miceli, R

AU - Nichetti, F.

AU - Cheli, Stefania

AU - Antoniotti, C.

AU - Infante, G.

AU - Martinetti, A

AU - Marmorino, Federica

AU - Sottotetti, E

AU - Berenato, R

AU - Caporale, M

AU - Colombo, A

AU - de Braud, F

AU - Di Bartolomeo, M

AU - Clementi, E

AU - Loupakis, F

AU - Pietrantonio, F

PY - 2016/3/22

Y1 - 2016/3/22

N2 - 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 (χ(2) test 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.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.22.

AB - 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 (χ(2) test 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.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.22.

KW - Journal Article

U2 - 10.1038/tpj.2016.22

DO - 10.1038/tpj.2016.22

M3 - Article

C2 - 27001121

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

ER -