The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue
The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue
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DOI：
10.1007/s00280-011-1751-4
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发表时间：
2012-03-01
影响因子：
3
通讯作者：
Sica, Simona
中科院分区：
文献类型：
--
作者：
Chiusolo, Patrizia;Giammarco, Sabrina;Sica, Simona
目的近年来，人们研究了不同基因对化疗药物代谢的影响。甲氨蝶呤（MTX）是治疗急性淋巴细胞白血病（ALL）、原发性中枢神经系统淋巴瘤（PCNSL）和伯基特淋巴瘤（BL）的关键化疗药物。本研究旨在评估MTHFR C677T和A1298C多态性和G80A还原叶酸载体基因（RFC 1）在接受大剂量MTX治疗的淋巴组织增生性恶性肿瘤成人患者队列中的作用。结果携带MTHFR A1298C变异体的患者肝毒性和血液毒性明显降低（P = 0.03）。RFC 1 G80A纯合子野生型和变异型患者的总生存期（OS）和无进展生存期（PFS）有显著差异（分别为P = 0.035和P = 0.02）。观察到血液学毒性与年龄之间存在显著相关性（P = 0.003）。MTHFR C677T基因型对MTX的毒性、OS和PFS无显著影响。结论MTX大剂量化疗后给予甲酰四氢叶酸补救可能是MTHFR C677T基因型对MTX毒性、OS和PFS无显著影响的原因。为了更好地确定RFC 1多态性对患者预后的作用，值得对不同基因型的细胞内MTX水平和RFC 1底物结合亲和力进行研究。
Purpose In the last years, the influence of different genes involved in metabolism of chemotherapeutic agents has been studied. Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL) and Burkitt's lymphomas (BL). This study aims to evaluate the role of MTHFR C677T and A1298C polymorphisms and G80A reduced folate carrier gene (RFC1) in a cohort of adult patients with lymphoproliferative malignancies submitted to high-dose MTX followed by leucovorin rescue.Methods We performed the analysis of these polymorphisms on genomic DNA with RFLP-PCR.Results Patients carrying MTHFR A1298C variant showed decreased hepatic and hematological toxicity (P = 0.03). Overall survival (OS) and progression-free survival (PFS) between homozygous wild-type and variant patients for the RFC1 G80A were significantly different (P = 0.035 and P = 0.02, respectively). A significant correlation between hematological toxicity and age (P = 0.003) was observed. There was no significant influence of MTHFR C677T genotype on toxicity, OS and PFS.Conclusions Leucovorin rescue given after high-dose MTX probably accounts for the lack of influence of C677T polymorphism. To better define a role of RFC1 polymorphism on patients outcome, it would be worthwhile to perform a study on intracellular MTX level and RFC1 substrate binding affinities in different genotypes.