Influence of XPC, XPD, XPF, and XPG gene polymorphisms on the risk and the outcome of acute myeloid leukemia in a Romanian population

Abstract

XPC, XPD, XPF, and XPG genes are implicated in the nucleotide excision repair (NER) system. Gene polymorphisms in NER repair system may influence the individual's capacity to recognize and repair DNA lesions, thus increasing the cancer risk. We hypothesized that these gene polymorphisms might influence the probability of developing acute myeloid leukemia (AML). We investigated the XPC, XPD, XPF, and XPG gene polymorphisms in 108 AML cases and 163 healthy controls. Also cytogenetic analyses besides FLT3 and DNMT3A mutations status were investigated. We found that variant genotypes (heterozygous and homozygous) of XPD 2251A > C and 22541A > C and the heterozygous genotype of XPG 3507G > C were associated with the risk of developing AML (OR = 2.55; 95% CI = 1.53-4.25; p value <0.001; OR = 1.66, 95 % CI = 1.02-2.72; p value = 0.047, and OR = 2.36; 95 % CI = 1.32-4.21; p value = 0.004, respectively). No association was found between white blood cell counts, FLT3, DNMT3A mutations, cytogenetic risk group, and variant genotypes of none of the analyzed polymorphisms. Variant homozygous XPF 673C > T genotype was associated with higher dose of cytosine arabinoside treatment administrated to AML patients (p value = 0.04). No differences were found regarding survival time and variant genotype in the investigated gene polymorphisms with the exception of XPD 2251A > C. In conclusion, XPD 22541A > C, XPD 2251A > C, and XPG 3507G > C gene polymorphisms confer susceptibility to AML, while XPC 2920A > C, XPF-673C > T, XPF 11985A > G are not associated with AML.

The Value of FLT3, NPM1 and DNMT3A Gene Mutation Analysis in Acute Myeloid Leukemia Diagnosis

“…Myeloid neoplasms, especially acute myeloid leukemia (AML), are characterized by abnormal proliferation of hematopoietic cells and by genomic instability with a high diversity of chromosomal and molecular abnormalities (1,2). The 2016 revised World Health Organization classification of AML and myeloid neoplasm emphasized the value of molecular genetics testing in AML risk stratification and prognosis, especially for patients with a normal karyotype (3,4).…”

Cytokine rs361525, rs1800750, rs1800629, rs1800896, rs1800872, rs1800795, rs1800470, and rs2430561 SNPs in relation with prognostic factors in acute myeloid leukemia

“…Acute myeloid leukemia (AML) is a complex and dynamic human malignancy characterized by multiple somatically‐acquired driver mutations, poor prognosis, and short survival, less than 20% of adult AML patients surviving 5 years after diagnosis …”

“…Acute myeloid leukemia (AML) is a complex and dynamic human malignancy characterized by multiple somatically-acquired driver mutations, poor prognosis, and short survival, less than 20% of adult AML patients surviving 5 years after diagnosis. 1,2 Cytokines (interleukins [ILs], growth factors, interferons, etc) play an important role in regulating the inflammatory response, and chronic inflammation and are involved in cancer development. 3,4 Chronic inflammation is associated with the release of various mediators (pro-inflammatory and oncogenic ones), such as reactive nitrogen oxygen species, inflammatory cytokines (IL-1β, IL-2, IL-6, and tumor necrosis factor alpha [TNF-α]), growth factors, and chemokines.…”

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

“…Carriership of these two polymorphisms has already been identified as a risk factor for development of leukaemia, increasing the risk > 2-fold for XPD Lys751Gln and > 3.5 fold for XRCC3 Thr241Met, respectively (Hamdy et al 2011, Bănescu et al 2014). Additional research is required in order to confirm the report of Diamond et al 2011, but it could be expected that some of the polymorphisms in other genes responsible for identification and repair of DNA damage and maintenance of genomic integrity that have been already implicated in the pathogenesis of leukaemia, such as TP53 Pro72Arg, MDM2 SNP309 (rs2279744), XRCC1 Arg194Trp (rs1799782), hOGG1 Ser326Cys (rs1052134), CCNH Val270Ala (rs2230641) (Enjuanes et al 2008, Batar et al 2009, Do et al 2009, Li et al 2011) and polymorphisms that have been associated with differential outcomes after haematological disease and HSC transplantations (the above mentioned TP53 Pro72Arg and also HMGB1 3814 C-to-G (rs2249825); XPC Lys939Gln (rs2228001) and XPF C673T (Kornblit et al 2010, McGraw et al 2015, Bănescu et al 2016) and potentially, others may modulate the risk for development of donor-cell leukaemia in patients with HSC transplantations. Carriership of the variant (deletion) allele of the -1377delA (rs41369348) polymorphism in the HMGB1 gene was associated with 2-fold increased risk of relapse of the primary haematological malignancy (Kornblit et al 2010).…”