Mutational Analysis of Ionizing Radiation Induced Neoplasms

SummaryIonizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma

Purpose: The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra–high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial.Methods: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS.Results: Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity.Conclusion: Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.</p

Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers

Background Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. Methods A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). Results Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival. Conclusions No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation

Balancing selection at the major histocompatibility complex (MHC) : sequence diversity and inbreeding avoidance

The major histocompatibility complex (MHC) is a much studied region of the mammalian genome because of its uniquely high level of polymorphism. Both natural and sexual selection have been implicated in the maintenance of MHC diversity. The elevated heterozygosity observed at the MHC could reflect overdominant heterozygote advantage against pathogenic infection. Equally, MHC disassortative mating would lead to an excess of heterozygotes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Balancing selection at the major histocompatibility complex (MHC) : sequence diversity and inbreeding avoidance

The major histocompatibility complex (MHC) is a much studied region of the mammalian genome because of its uniquely high level of polymorphism. Both natural and sexual selection have been implicated in the maintenance of MHC diversity. The elevated heterozygosity observed at the MHC could reflect overdominant heterozygote advantage against pathogenic infection. Equally, MHC disassortative mating would lead to an excess of heterozygotes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo