Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies

Abstract

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C4T, 1298A4C), involved in DNA synthesis. The analyzed groups were a t-MDS/ AML patients group (n ¼ 81) and a matched control group (n ¼ 64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P ¼ 0.016) and cyclophosphamide-treated hematological disease group (P ¼ 0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.

Associations of NQO1 C609T and NQO1 C465T polymorphisms with acute leukemia risk: a PRISMA-compliant meta-analysis

“…Among these studies, 11 focused on Caucasians,1,3,12–20 10 on Asians,2,9,10,21–27 four on mixed populations,5,28–30 two on Africans,31,32 and one on Javanese 33. In terms of the genotype distribution of controls, 20 of the studies about the association between the NQO1 C609T polymorphism and the AL risk conformed with HWE,1,3,5,9,12,14–20,22–24,28,30–33 while seven did not,2,10,21,25–27,29 and the HWE test could not be applied to one study13 because of insufficient data. Two studies of the association between the NQO1 C465T polymorphism and the AL risk conformed with HWE,16,9 while two did not 23,24.…”

Second primary malignancies of cancer patients: treatment-related carcinogenesis

“…Ее полиморфизм в случае гомозиготной мутации C677T, препятствую-щей связыванию фолата, коррелирует с нарушением репарации ДНК, наличием хромосомных аберраций в клетках гемопоэза и повышенной частотой возник-новения лекарственных миелолейкозов. В частности, в одном из исследований такое отдаленное осложнение значительно чаще возникало у больных с однонуклео-тидным полиморфизмом 677 и 1298 (гаплотип 677T1298A) после лечении рака молочной железы и у пациентов с гаплотипом 677C1298C после лечения онкологиче-ских заболеваний кроветворной системы [50].…”

Treatment related myeloid malignancies in childhood

“…Low thiopurine-methyltransferase activity and polymorphism of a CYP3A4 enzyme results in as DNA-damaging metabolite of epipodophyllotoxins [38,76,77]. Also glutathione-S-transferase, NAD(P)H: quinine oxireductase and polymorphisms of DNA repair genes are linked with an increased occurrence of t-AML/MDS [28,36,[78][79][80][81][82][83][84][85][86][87]. Extensive reviews on genetic susceptibility and biological pathogenesis were published [21,56,66,82].…”