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Open Access Research article

Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients

Joana Savva-Bordalo14, João Ramalho-Carvalho24, Manuela Pinheiro25, Vera L Costa24, Ângelo Rodrigues3, Paula C Dias3, Isabel Veiga25, Manuela Machado1, Manuel R Teixeira256, Rui Henrique346 and Carmen Jerónimo246*

Author Affiliations

1 Department of Medical Oncology, Portuguese Oncology Institute - Porto, Portugal

2 Department of Genetics, Portuguese Oncology Institute - Porto, Portugal

3 Department of Pathology, Portuguese Oncology Institute - Porto, Portugal

4 Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Portugal

5 Cancer Genetics Group, Research Center of the Portuguese Oncology Institute - Porto, Portugal

6 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal

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BMC Cancer 2010, 10:470  doi:10.1186/1471-2407-10-470

Published: 1 September 2010

Abstract

Background

Severe toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD).

Methods

In this study, we evaluated DPYD promoter methylation through quantitative methylation-specific PCR and screened DPYD for large intragenic rearrangements in peripheral blood from 45 patients with gastrointestinal cancers who developed severe 5-FU toxicity. DPYD promoter methylation was also assessed in tumor tissue from 29 patients

Results

Two cases with the IVS14+1G > A exon 14 skipping mutation (c.1905+1G > A), and one case carrying the 1845 G > T missense mutation (c.1845G > T) in the DPYD gene were identified. However, DPYD promoter methylation and large DPYD intragenic rearrangements were absent in all cases analyzed.

Conclusions

Our results indicate that DPYD promoter methylation and large intragenic rearrangements do not contribute significantly to the development of 5-FU severe toxicity in gastrointestinal cancer patients, supporting the need for additional studies on the mechanisms underlying genetic susceptibility to severe 5-FU toxicity.