Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?
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Date
2018-07-01ICR Author
Author
Pawlyn, C
Loehr, A
Ashby, C
Tytarenko, R
Deshpande, S
Sun, J
Fedorchak, K
Mughal, T
Davies, FE
Walker, BA
Morgan, GJ
Type
Journal Article
Metadata
Show full item recordAbstract
PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.
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Subject
Humans
Multiple Myeloma
Prognosis
Proportional Hazards Models
DNA Repair
Loss of Heterozygosity
Kaplan-Meier Estimate
Homologous Recombination
Biomarkers, Tumor
Poly(ADP-ribose) Polymerase Inhibitors
Research team
Myeloma Biology and Therapeutics
Language
eng
Date accepted
2017-12-15
License start date
2018-07
Citation
Leukemia, 2018, 32 (7), pp. 1561 - 1566
Publisher
NATURE PUBLISHING GROUP