No association between the XPD Lys751Gln (rs13181) polymorphism and disease phenotype or leukemic transformation in primary myelofibrosis

Abstract

Philadelphia negative (Ph -) classical myeloproliferative neoplasms (MPNs), i.e. polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders of hematopoiesis with high frequency of recurrent somatic gene mutations, like JAK2V617F and MPLW515L, DNA copy variations, and chromosomal aberrations.1,2 Consequently, the neoplastic process is thought to be initiated, maintained, and enhanced by acquired molecular lesions. However, germ-line variants, like the 46/1 haplotype of the JAK2 gene [3][4][5][6] or the A3669G single nucleotide polymorphism (SNP) of glucocorticoid receptor, 7 have been documented to predispose to the acquisition of the mutations or the diseases themselves, and to determine their phenotype and outcome.Recently, Hernandez-Boluda and co-workers have identified a polymorphism in the xeroderma pigmentosum group D (XPD) gene, rs 13181, reporting it to be an independent risk factor for leukemic transformation in ET and PV.8 Specifically, homozygous carriers for the minor allele (Gln/Gln) had an almost 5-fold higher risk of progression to acute myeloid leukemia (AML) compared with the other XPD genotypes. In addition, the Gln/Gln XPD variant was associated with a 4-fold increased risk of developing a new primary non-myeloid malignancy during follow up, regardless of the type of treatment given to the patients.PMF shares with ET and PV an increased risk of leukemic transformation which occurs in 15-20% of patients; 9 more frequently, therefore, than in PV or ET where it occurs in 5-10% of patients.10-12 We analyzed the XPD Lys751Gln (rs13181) polymorphism in a representative cohort of PMF patients in order to evaluate its contribution to the hematologic malignancy and whether it could influence the likelihood of developing AML. The cohort was made up of 456 consecutive patients with World Health Organization defined PMF enrolled in our patient database from 2000 to 2012.13 The control group was made up of 138 Italian individuals without any hematologic malignancies. The ethics committee of the Policlinico San Matteo Foundation, Pavia, Italy, had approved the informed consent for PMF patients to donate samples for molecular research on their disease, and all patients signed this consent form before sampling. The normal control population was made up of healthy Italian subjects belonging to the bone marrow donor registry whose samples were made anonymous for the purpose of the study.The genomic DNA was isolated from blood granulocytes of all patients and controls, obtained using the QIAamp DNA Blood Mini Kit (QIAGEN, Duesseldorf, Germany). The rs13181 SNP was genotyped by real-time polymerase chain reaction (PCR) using the TaqMan SNP genotyping on demand assay C-3145033-10 (Life Technologies Corporation, Paisley, UK). Assays were performed according to the manufacturer's instructions. JAK2V617F mutation and allele burden were determined by RTq PCR. 14The genotypes and allele distribution of the Lys751Gln SNP were compared between PMF patients and controls us...

The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms

“…Exposure to cytoreductive treatments, patient age, and leukocytosis at diagnosis are considered risk factors for progression to acute leukemia in patients with PV and ET [ 60 ]. In contrast, the research conducted by Poletto et al which included 456 Italian MFP patients did not report any association between XPD 2251A>C and the risk of leukemic transformation [ 34 ].…”

“…There is a change at codon 751 in exon 23 from lysine to glutamine [ 30 ]. XPD 2251A>C polymorphism contributes to hematological neoplasms, such as chronic myeloid leukemia (CML) [ 32 , 33 ], AML [ 29 ], and AML transformation [ 26 ], and some showed no association [ 34 , 35 , 36 ].…”

Focused screening of a panel of cancer‐related genetic polymorphisms reveals new susceptibility loci for pediatric acute lymphoblastic leukemia

“…Inherited variations in DNA‐repair efficiency have been implicated in the predisposition to de novo and therapy‐related AML . Moreover, Hernandez‐Boluda et al identified rs13181 in ERCC2 as an independent risk factor for leukemic transformation in primary myelofibrosis, even though their finding is not without controversy . Several reports linked polymorphisms in the ERCC2 gene with enhanced risk of childhood ALL , although negative results were also reported .…”