Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients.
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.
Savva-Bordalo
Joana
J
Department of Medical Oncology, Portuguese Oncology Institute - Porto, Portugal.
Ramalho-Carvalho
João
J
Pinheiro
Manuela
M
Costa
Vera L
VL
Rodrigues
Angelo
A
Dias
Paula C
PC
Veiga
Isabel
I
Machado
Manuela
M
Teixeira
Manuel R
MR
Henrique
Rui
R
Jerónimo
Carmen
C
D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005770:Gastrointestinal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
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