ABCB1 c.3435C>T polymorphism is associated with platinum toxicity

a preliminary study

Beatrice De Troia, Davide Dalu, Virginio Filipazzi, Luigi Isabella, Nicoletta Tosca, Sabrina Ferrario, Anna Rita Gambaro, Luisa Somma, Cinzia Fasola, Stefania Cheli, Emilio Clementi, Davide De Francesco, Felicia Stefania Falvella, Maria Teresa Cattaneo

Research output: Contribution to journalArticle

Abstract

Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings. Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage II–IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by real-time PCR. We selected and analyzed three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results: Variant alleles were present in 53% of patients for ABCB1 c.3435C >T, 18.3% for ABCC2 -24C> T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95% CI 0.05, 0.69; p = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95% CI 0.09, 0.79; p = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism. Conclusions: The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.

Original languageEnglish
JournalCancer Chemotherapy and Pharmacology
DOIs
Publication statusPublished - Jan 1 2019

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Platinum
Polymorphism
Toxicity
Single Nucleotide Polymorphism
Carboplatin
Nucleotides
Cisplatin
Nucleotide Mapping
Lung Neoplasms
Chemotherapy
Alleles
Genotype
Drug Therapy
Genetic Models
Small Cell Lung Carcinoma
Drug-Related Side Effects and Adverse Reactions
Informed Consent
Terminology
Epigenomics
Real-Time Polymerase Chain Reaction

Keywords

  • Efflux transporters
  • Genetic factors
  • Lung cancer
  • Platinum
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

De Troia, B., Dalu, D., Filipazzi, V., Isabella, L., Tosca, N., Ferrario, S., ... Cattaneo, M. T. (2019). ABCB1 c.3435C>T polymorphism is associated with platinum toxicity: a preliminary study. Cancer Chemotherapy and Pharmacology. https://doi.org/10.1007/s00280-019-03794-6

ABCB1 c.3435C>T polymorphism is associated with platinum toxicity : a preliminary study. / De Troia, Beatrice; Dalu, Davide; Filipazzi, Virginio; Isabella, Luigi; Tosca, Nicoletta; Ferrario, Sabrina; Gambaro, Anna Rita; Somma, Luisa; Fasola, Cinzia; Cheli, Stefania; Clementi, Emilio; De Francesco, Davide; Falvella, Felicia Stefania; Cattaneo, Maria Teresa.

In: Cancer Chemotherapy and Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

De Troia, B, Dalu, D, Filipazzi, V, Isabella, L, Tosca, N, Ferrario, S, Gambaro, AR, Somma, L, Fasola, C, Cheli, S, Clementi, E, De Francesco, D, Falvella, FS & Cattaneo, MT 2019, 'ABCB1 c.3435C>T polymorphism is associated with platinum toxicity: a preliminary study', Cancer Chemotherapy and Pharmacology. https://doi.org/10.1007/s00280-019-03794-6
De Troia, Beatrice ; Dalu, Davide ; Filipazzi, Virginio ; Isabella, Luigi ; Tosca, Nicoletta ; Ferrario, Sabrina ; Gambaro, Anna Rita ; Somma, Luisa ; Fasola, Cinzia ; Cheli, Stefania ; Clementi, Emilio ; De Francesco, Davide ; Falvella, Felicia Stefania ; Cattaneo, Maria Teresa. / ABCB1 c.3435C>T polymorphism is associated with platinum toxicity : a preliminary study. In: Cancer Chemotherapy and Pharmacology. 2019.
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abstract = "Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings. Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage II–IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by real-time PCR. We selected and analyzed three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results: Variant alleles were present in 53{\%} of patients for ABCB1 c.3435C >T, 18.3{\%} for ABCC2 -24C> T, and 34.8{\%} for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95{\%} CI 0.05, 0.69; p = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95{\%} CI 0.09, 0.79; p = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism. Conclusions: The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.",
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T1 - ABCB1 c.3435C>T polymorphism is associated with platinum toxicity

T2 - a preliminary study

AU - De Troia, Beatrice

AU - Dalu, Davide

AU - Filipazzi, Virginio

AU - Isabella, Luigi

AU - Tosca, Nicoletta

AU - Ferrario, Sabrina

AU - Gambaro, Anna Rita

AU - Somma, Luisa

AU - Fasola, Cinzia

AU - Cheli, Stefania

AU - Clementi, Emilio

AU - De Francesco, Davide

AU - Falvella, Felicia Stefania

AU - Cattaneo, Maria Teresa

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings. Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage II–IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by real-time PCR. We selected and analyzed three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results: Variant alleles were present in 53% of patients for ABCB1 c.3435C >T, 18.3% for ABCC2 -24C> T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95% CI 0.05, 0.69; p = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95% CI 0.09, 0.79; p = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism. Conclusions: The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.

AB - Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings. Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage II–IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by real-time PCR. We selected and analyzed three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results: Variant alleles were present in 53% of patients for ABCB1 c.3435C >T, 18.3% for ABCC2 -24C> T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95% CI 0.05, 0.69; p = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95% CI 0.09, 0.79; p = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism. Conclusions: The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.

KW - Efflux transporters

KW - Genetic factors

KW - Lung cancer

KW - Platinum

KW - Toxicity

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