dc.contributor.author | Pawlyn, C | |
dc.contributor.author | Loehr, A | |
dc.contributor.author | Ashby, C | |
dc.contributor.author | Tytarenko, R | |
dc.contributor.author | Deshpande, S | |
dc.contributor.author | Sun, J | |
dc.contributor.author | Fedorchak, K | |
dc.contributor.author | Mughal, T | |
dc.contributor.author | Davies, FE | |
dc.contributor.author | Walker, BA | |
dc.contributor.author | Morgan, GJ | |
dc.date.accessioned | 2018-12-04T12:46:37Z | |
dc.date.issued | 2018-07-01 | |
dc.identifier.citation | Leukemia, 2018, 32 (7), pp. 1561 - 1566 | |
dc.identifier.issn | 0887-6924 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2965 | |
dc.identifier.eissn | 1476-5551 | |
dc.identifier.doi | 10.1038/s41375-018-0017-0 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1561 - 1566 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Multiple Myeloma | |
dc.subject | Prognosis | |
dc.subject | Proportional Hazards Models | |
dc.subject | DNA Repair | |
dc.subject | Loss of Heterozygosity | |
dc.subject | Kaplan-Meier Estimate | |
dc.subject | Homologous Recombination | |
dc.subject | Biomarkers, Tumor | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.title | Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition? | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-12-15 | |
rioxxterms.versionofrecord | 10.1038/s41375-018-0017-0 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Leukemia | |
pubs.issue | 7 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Myeloma Biology and Therapeutics | |
pubs.publication-status | Published | |
pubs.volume | 32 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Myeloma Biology and Therapeutics | |
dc.contributor.icrauthor | Pawlyn, Charlotte | |