<i>PARP1</i> and <i>POLD2</i> as prognostic biomarkers for multiple myeloma in autologous stem cell transplant
Melissa Thomas,
Junan Li,
Kevan King,
Avinash K Persaud,
Ernest Duah,
Zachary Vangundy,
Craig C. Hofmeister,
Jatinder K. Lamba,
Aik Choon Tan,
Brooke L. Fridley,
Ming J. Poi,
Nathan D. Seligson
Affiliations
Melissa Thomas
Department of Pharmacotherapy and Translational Research, The University of Florida, Jacksonville, FL
Junan Li
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Kevan King
Department of Pharmacotherapy and Translational Research, The University of Florida, Jacksonville, FL
Avinash K Persaud
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH
Ernest Duah
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH
Zachary Vangundy
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH
Craig C. Hofmeister
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
Jatinder K. Lamba
Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, FL
Aik Choon Tan
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Brooke L. Fridley
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Ming J. Poi
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Nathan D. Seligson
Department of Pharmacotherapy and Translational Research, The University of Florida, Jacksonville, FL, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Center for Pharmacogenomics and Translational Research, Nemours Children’s Health, Jacksonville, FL
Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatment-dependent. In preclinical models of MM, synergy was observed in anti-tumor activity when poly (ADPribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan-sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.
