Research On SNPs Of DPYD Gene In Breast Cancer Chemotherapy

Objective DPYD is an important drug catabolish gene and lots of variants have been reported.Several researchs have demonstrated the association between DPYD single nucleotide polymorphisms and the prognosis of cancer.But those studies mainly in gastric cancer and coloretal cancer,there is less study reported in breast cancer and no report has been found in breast cancer of China.In our study,the genotype of DPYD was detected in 187 cases of breast cancer.We demonstrated the genotype frequency of Chinese breast cancer patients.DPD is encoded by the DPYD gene,and is the first rate-limiting enzyme in the metabolic pathway of fluoropyrimidines and pyrimidine.DPD may involve in the occurrence of breast cancer,and associate with the sensitivity of chemotherapy,and it may have effect on the prognosis of patients.In the project,we focus on the association between DPYD SNPs and prognosis of breast cancer.We hope the result could provide an effective strategy for the treatment of breast cancer.Methods 1.Paraffin-embedded tissue of 187 patients from Department of Breast Cancer Pathology and Research Laboratory,Tianjin Medical University Cancer Institute & Hospital were collected,patients were followed up.2.5 DPYD SNPs status(c.74A>G,c.85T>C,c.1627A>G,c.1896T>C and c.2194G>A)were determined using the Diagnostic Kit for DPYD Mutation(Da An Gene,China).3.Observed the genotype frequencies of DPYD SNPs in 187 breast cancer patients.4.The association between DPYD SNPs and clinical pathological features was analysed by SPSS 17.0.5.The predictive value of DPYD genotype for the progression of breast cancer patients was evaluated.Results 1.The alleles and genotypic frequencies of DPYD SNPs in 187 breast cancer specimens were as follows: For the DPYD c.74A>G polymorphism,GG,AG and AA genotype were 2.7%,0 and 97.3%,respectively.For the DPYD c.85T>C polymorphism,CC,TC and TT genotype were 1.6%,13.4%,85.0%,respectively.In the c.1627A>G polymorphism,GG,AG and AA genotype were 7.0%,29.9% and 63.1%,respectively.For the DPYD c.1896T>C polymorphism,CC,TC and TT genotype were 2.1%,22.5%,75.4%,respectively.For the DPYD c.2194G>A polymorphism,GG,GA and AA genotype were 96.8%,3.2% and 0,respectively.2.We found that DPYD mutant genotype was negatively correlated with tumor stage(rs=-0.172,P=0.023)and not correlated with other clinicopathological characteristics.3.We compared the clinical outcome of patients with wild type or non-wild type DPYD.No obvious difference of the clinical outcome was found between patients with wild type or mutant DPYD(P<0.05).4.Mutant DPYD carriers treated with fluoropyrimidine-based chemotherapy exhibited a shorter OS and PFS compared with carriers with non-fluoropyrimidine chemotherapy(P<0.05).5.In non-luminal subgroup,mutant DPYD carriers treated with fluoropyrimidine-based chemotherapy exhibited a worse prognosis compared with carriers with non-fluoropyrimidine chemotherapy(P<0.05).6.The clinical significance of 3 SNPs(c.85T>C,c.1627A>G,c.1896T>C)was analyzed,individually.For c.1627A>G AG/GG genotype,patients treated with fluoropyrimidine-based chemotherapy exhibited a shorter OS compared with those treated with non-fluoropyrimidine(P=0.005).For c.85T>C TC/CC genotype,patients treated with fluoropyrimidine-based chemotherapy exhibited a shorter PFS compared with those treated with non-fluoropyrimidine(P=0.037).7.For non-luminal subtype,c.1627A>G AG/GG genotype carriers treated with fluoropyrimidine-based chemotherapy showed a shorter OS and PFS compared with carriers treated with non-fluoropyrimidine(P<0.05).Meanwhile,c.1896T>C TC/CC genotype carriers treated with fluoropyrimidine-based chemotherapy exhibited a shorter OS compared with those treated withnon-fluoropyrimidine(P=0.009).8.We found that mutant DPYD carriers treated with TE-based regimen exhibited a longer OS compared with carriers treated with non-TE regimen(P=0.001).9.The clinical significance of 3 SNPs was analyzed.For c.1627A>G AG/GG genotype,patients treated with TE-based chemotherapy exhibited an increased OS compared with those treated with non-TE regimen(P=0.032).For c.1896T>C TC/CC genotype,patients treated with TE-based chemotherapy exhibited an increased OS compared with those treated with non-TE regimen(P=0.029).10.For non-luminal subtype patients with c.1627A>G AG/GG genotype,those treated with TE-based chemotherapy exhibited a better OS compared with patients treated with non-TE chemotherapy(P=0.015).Conclusion 1.The observed genotype frequencies of c.85T>C,c.1627A>G and c.1896T>C were higer in breast cancer patients.2.DPYD mutant genotype was negatively correlated with tumor stage(rs=-0.172,P=0.023).3.For non-luminal subtype,c.1627A>G AG/GG genotype carriers treated with fluoropyrimidine-based chemotherapy showed a worse prognosis compared with carriers treated with non-fluoropyrimidine chemotherapy.Those carriers treated with fluoropyrimidine-based chemotherapy showed a better prognosis compared with carriers treated with non-fluoropyrimidine chemotherapy.