PARP1 V762A polymorphism affects the prognosis of myelodysplastic syndromes

Abstract

Objective: Myelodysplastic syndromes (MDS), caused by various genetic mutations in hematopoietic stem cells, are associated with highly variable outcomes. Poly (ADP-ribose) polymerase-1 (PARP1) plays an important role in DNA damage repair and contributes to the progression of several types of cancer. Here, we investigated the impact of PARP1 V762A polymorphism on the susceptibility to and prognosis of MDS.Methods: Samples collected from 105 MDS patients and 202 race-matched healthy controls were subjected to polymerase chain reaction-restriction fragment length polymorphism for genotyping. Results:The allele and genotype frequencies of PARP1 V762A did not differ between MDS patients and the control group. However, MDS patients with the PARP1 V762A non-AA genotype, which is associated with high gene activity, had shorter overall survival rates (P = .01) than those with the AA genotype. Multivariate analysis of overall survival also revealed PARP1 V762A non-AA genotype as a poor prognostic factor (P = .02). When patients were analyzed according to treatment history, the PARP1 V762A non-AA genotype was only associated with poor survival in patients who had received treatment (P = .02).Conclusion: PARP1 V762A polymorphism may be an independent prognostic factor for MDS, and a predictive biomarker for MDS treatment. K E Y W O R D S myelodysplastic syndromes, PARP1, polymorphism | 527 GOTOH eT al.

Common and rare variant associations with clonal haematopoiesis phenotypes

“…Both PARP1 and LY75 contain missense variants associated with reduced risk of CHIP and of DNMT3A CHIP specifically. The variants in the PARP1 locus are significantly associated with reduced PARP1 gene expression in whole blood 32 ( P ≤ 1 × 10 −13 ), and the V762A missense variant (rs1136410-G) has been recently reported to associate with improved prognosis and survival in MDS 18 . Given the well-established role of PARP1 in DNA repair 33 , and that a recent CRISPR screen study in zebrafish identified PARP1 inhibition as a selective killer of TET2 mutant haematopoietic stem cells 34 , it seems plausible that a therapeutic strategy that inhibits PARP1 might be viable for the antagonization of CHIP clone expansion.…”

“…PARP1 has a role in DNA damage repair, and many variants in this block have been identified across multiple transcriptomic studies of blood as PARP1 expression quantitative trait loci (eQTLs) that associate with reduced PARP1 gene expression [14][15][16][17] . Furthermore, a missense variant (rs1136410-G, V762A) that is predicted as likely to be damaging (combined annotation dependent depletion (CADD) score = 27.9) is a part of this LD block, and has recently been reported to associate with improved prognosis and survival in myelodysplastic syndromes 18 (MDS). At a locus on chromosome 2, rs78446341 (P1247L in LY75) was associated with reduced risk of DNMT3A CHIP (odds ratio = 0.78 [0.72-0.84], P = 3.70 × 10 −10 ), and was prioritized by fine-mapping (Extended Data Fig.…”

“…Although we have taken many steps to ensure the quality of our callset and analysis (Supplementary Notes 11 and 12 and Supplementary Figs. [15][16][17][18], the misclassification of somatic variants with high VAF as germline variants, and/or the misclassification of true germline variants as somatic clonal haematopoiesis variants (for example, germline variants at genomic positions identified as clonal haematopoiesis hotspots) remain challenges inherent to calling and analysing CHIP and clonal haematopoiesis when using population scale genomic data. Serial sampling would enable the evaluation of changes to CHIP clones over time, and future studies that focus on such serial analysis at large scale will be able to better estimate CHIP subtype-specific clonal changes and clinical risk.…”

Genetic Predisposition to Clonal Hematopoiesis

“…36 Notably, the rs1136410 variant has been identified as a prognostic factor and predictive biomarker for MDS. 37 These data suggest that PARPi may have the effect of reducing or reversing CH clonal expansion of clones driven by DNMT3A mutations.…”

Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

“…Both PARP1 and LY75 have missense variants that are associated with a reduced risk of DNMT3A -CHIP. The PARP1 missense variant (rs1136410-G, V762A) is also a significant expression reducing eQTL in whole blood (P = 7.2 × 10 −17 ) 14 , and has been recently reported to associate with improved prognosis and survival in MDS 30 . Given the well-established role of PARP1 in DNA repair 31 , and the approval and application of PARP1 inhibiting drugs for the treatment of BRCA-positive cancers 32 , it seems plausible that a PARP1 expression reducing eQTL might antagonize CHIP clone expansion.…”