A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera

Hernández‐Boluda, Juan‐Carlos; Pereira, Arturo; Cervantes, Francisco; Alvarez‐Larrán, Alberto; Collado, María; Such, Esperanza; Arilla, M. Jesús; Boqué, Concepción; Xicoy, Blanca; Maffioli, Margherita; Bellosillo, Beatríz; Marugán, Isabel; Amat, Paula; Besses, Carles; Guillem, Vicent

doi:10.1182/blood-2012-02-411215

Cited by 35 publications

(41 citation statements)

References 41 publications

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“…In particular, we did not find any predisposition toward AML transformation attributable to the polymorphism. This latter finding is at variance with that reported by Hernandez-Boluda in PV and ET, 8 and reinforces the hypothesis that the pathogenesis of AML in PMF is due to complex oncogenic events that differ from those affecting AML transformation in PV and ET disorders. …”

Section: Observed Frequency or (95%ci) Global (N=456) Xpd A/a +A/c (Nsupporting

confidence: 82%

“…8 The XPD protein has an important role in the nucleotide excision repair pathway and is also involved in transcription initiation and control of cell cycle. 16 The variant had been previously associated with outcome after chemotherapy for acute leukemia and also found to predict for an increased risk of developing leukemia after chemotherapy.…”

Section: Observed Frequency or (95%ci) Global (N=456) Xpd A/a +A/c (Nmentioning

confidence: 99%

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

et al. 2013

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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...

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Section: Observed Frequency or (95%ci) Global (N=456) Xpd A/a +A/c (Nsupporting

confidence: 82%

Section: Observed Frequency or (95%ci) Global (N=456) Xpd A/a +A/c (Nmentioning

confidence: 99%

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

et al. 2013

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“…[3][4][5][6][7][8][9][10][11][12][13][14] In this study, we focused on the A3669G (rs6198) polymorphism of the GR gene in PMF because its frequency has been reported to be increased in PV patients, and the variant has been documented to be able to induce an excess proliferative signaling in hematopoietic cells. 15 With a large cohort of patients with WHO-classified PMF, in this study we provide evidence that the A3669G SNP represents a host predisposition factor for PMF.…”

Section: Discussionmentioning

confidence: 99%

“…11 Hernández-Boluda et al documented a strong association with leukemia and primary nonmyeloid cancers of the Gln/Gln genotype in the codon 751 of the DNA repair XPD gene in ET and PV patients. 12 Other polymorphisms were investigated as host-modifying factors in MPNs, such as TP53 exon 4 codon 72 in PMF 13 and MDM2 SNP 309 in members of families with MPN. 14 However, in these cases, the allele frequencies were not different from the general population, and the SNPs did not determine different presenting characteristics or survival or predispose to hereditary diseases.…”

Section: Introductionmentioning

confidence: 99%

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Poletto

Rosti

Villani

et al. 2012

Blood

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The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34 ؉ cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P ‫؍‬ .049) and blast transformation (BT)-free survival (76.7 months vs 261 months; P ‫؍‬ .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio ‫؍‬ 3.3; P ‫؍‬ .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT. (Blood. 2012; 120(15):3112-3117)

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“…However, the frequency of the GGCC haplotype was found to be similar for the familial and sporadic MPN cases, and thus, it cannot explain familial clustering of MPN [159]. With respect to disease progression, a coding polymorphism in the codon 751 of XPD gene was shown to be associated with leukemic transformation as well as development of non-myeloid malignancies in patients with PV and ET [160]. Furthermore, germline mutations in regions of somatic loss of heterozygosity may exert a phenotypic effect in blood cells and modulate the MPN phenotype [161].…”

Section: Familial Myeloproliferative Neoplasmsmentioning

confidence: 99%

Genetic and epigenetic alterations of myeloproliferative disorders

Milosevic

Královics

2012

Int J Hematol

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The classical BCR-ABL negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are clonal hematopoietic disorders characterized by excessive production of terminally differentiated myeloid cells. In MPN patients, the disease can progress to secondary myelofibrosis or acute myeloid leukemia. Clonal hematopoiesis, disease phenotype, and progression are caused by somatically acquired genetic lesions of genes involved in cytokine signaling, RNA splicing, as well as epigenetic regulation. This review provides an overview of point mutations and cytogenetic lesions associated with MPN and addresses the role of these somatic lesions in MPN disease progression.

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A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera

Cited by 35 publications

References 41 publications

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

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

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Genetic and epigenetic alterations of myeloproliferative disorders

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