Blood
Development of Hyperdiploidy Starts at an Early Age and Takes a Decade to Complete
Samur MK, Aktas Samur A, Shah P, Park J, Fulciniti M, Shammas MA, Anderson KC, Parmigiani G, Munshi NC
Nearly half of multiple myeloma (MM) patients have hyperdiploidy (HMM) at diagnosis. Although HMM occurs early, the mutational processes before and after hyperdiploidy are still unclear. Here, we used 72 WGS samples from patients with HMM and identified pre and post HMM mutation to define the chronology of development of hyperdipoidy. A MM cell accumulated on median 0.56 mutations per mb pre-HMM and for every clonal pre-HMM mutation, 1.21 mutations accumulated post-HMM. This analysis using mutations before and after hyperdiploidy show that hyperdiploidy happens after somatic hypermutation, pre-hyperdipoidy muations are AID and age/Clock-like signature driven whereas post-hyperdiploidy mutations are from DNA damage and APOBEC. Interestingly, the first hyperdiploidy event occured within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations pre initiating event affected chromosomes at different rates while post-initiating event mutational processes affect each chromosomes equally.
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Blood
Serum Free Light Chains in a Racially Diverse Population Including African Americans and Populations from South Africa
Bertamini L, Alberge JB, Lee DJ, Kim S, Fleming G, Murphy CSM, Colchie J, Davis MI, Perry J, Lightbody ED, Allam S, Getz G, Karlson EW, Munshi NC, Anderson KC, Trippa L, Marinac CR, Ghobrial IM
Detection of light chain (LC) monoclonal gammopathies (MG) traditionally relies on serum free LC (FLC) k, A, and their ratio (k/A) reference ranges based on a mostly White population. We investigated FLC values in a racially diverse population by screening 10,035 individuals for heavy chain MG, identifying 9,028 negative cases whose FLC were measured. Participants included 4,149 from the PROMISE Study (US, n=2,383; South Africa, n=1,766) and 4,879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1,074 out of 10,035 individuals (10.7%) were diagnosed with LC-MGUS, with 99% being k-restricted. In the US, 14.8% of Black and 4% of White individuals were diagnosed (p<0.01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (p<0.01). Among South Africans (100% Black), 27.8% were diagnosed using standard ranges. To avoid overdiagnosis, we propose a new k/A ratio reference range (0.686 to 2.10) for populations of African descent with normal renal function, with standard values for k and A being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs. 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being k-restricted, consistent with LC myeloma rates. These findings highlight the importance of basing disease definitions, such as MGUS, on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences.
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Journal of the National Cancer Institute
Childhood, Adolescent and Young Adulthood Cancer Risk in BRCA1 or BRCA2 Pathogenic Variant Carriers
Rebbeck TR, Diller LR
BACKGROUND: Whether carriers of BRCA1 or BRCA2 (BRCA1/2) pathogenic variants (PVs) have increased risks of childhood, adolescent, and young adult (CAYA) cancers is controversial. We aimed to evaluate this risk and to inform clinical care of young BRCA1/2 PV carriers and genetic testing for CAYA cancer patients.
METHODS: Using data from 47,117 individuals from 3,086 BRCA1/2 families, we conducted pedigree analysis to estimate relative risks (RRs) for cancers diagnosed before age 30.
RESULTS: Our data included 274 cancers diagnosed before age 30: 139 breast cancers, 10 ovarian cancers, and 125 non-breast non-ovarian cancers. Associations for breast cancer in young adulthood (20-29 years) were found with RRs of 11.4 (95% CI: 5.5, 23.7) and 5.2 (95% CI: 1.6, 17.7) for BRCA1 and BRCA2 PV carriers, respectively. No association was found for any other investigated CAYA cancer, nor for all non-breast non-ovarian cancers combined: the RRs were 0.4 (95% CI: 0.1, 1.4) and 1.4 (95% CI: 0.7, 3.0) in BRCA1 or BRCA2 PV carriers, respectively.
CONCLUSION: We found no evidence that BRCA1/2 PV carriers have an increased CAYA cancer risk aside from breast cancer in women in their 20's. Our results, along with a critical evaluation of previous germline sequencing studies, suggest that the childhood and adolescent cancer risk conferred by BRCA1/2 PV would be low (ie, RR?<?2) if it existed. Our findings do not support PV testing for offspring of BRCA1/2 PV carriers at ages <18 years, nor for conducting BRCA1/2 PV testing for childhood and adolescent cancer patients.
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Nature Cancer
Evolving Cell States and Oncogenic Drivers During the Progression of IDH-Mutant Gliomas
Wu J, Gonzalez Castro LN, Battaglia S, El Farran CA, D'Antonio JP, Miller TE, Suvà ML, Bernstein BE
Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of 'permissive' chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.
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Nature Communications
Haploinsufficiency at the CX3CR1 Locus of Hematopoietic Stem Cells Favors the Appearance of Microglia-Like Cells in the Central Nervous System of Transplant Recipients
Montepeloso A, Mattioli D, Pellin D, Peviani M, Genovese P
Transplantation of engineered hematopoietic stem/progenitor cells (HSPCs) showed curative potential in patients affected by neurometabolic diseases treated in early stage. Favoring the engraftment and maturation of the engineered HSPCs in the central nervous system (CNS) could allow enhancing further the therapeutic potential of this approach. Here we unveil that HSPCs haplo-insufficient at the Cx3cr1 (Cx3cr1-/+) locus are favored in central nervous system (CNS) engraftment and generation of microglia-like progeny cells (MLCs) as compared to wild type (Cx3cr1+/+) HSPCs upon transplantation in mice. Based on this evidence, we have developed a CRISPR-based targeted gene addition strategy at the human CX3CR1 locus resulting in an enhanced ability of the edited human HSPCs to generate mature MLCs upon transplantation in immunodeficient mice, and in lineage specific, regulated and robust transgene expression. This approach, which benefits from the modulation of pathways involved in microglia maturation and migration in haplo-insufficient cells, may broaden the application of HSPC gene therapy to a larger spectrum of neurometabolic and neurodegenerative diseases.
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New England Journal of Medicine
Immunotherapy for Early-Stage Triple-Negative Breast Cancer
Burstein HJ
Early-stage triple-negative breast cancers, which lack expression of three proteins (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2), have long been defined by what they are not. Now they have found a new identity and treatment approach: they are breast cancers that benefit from immune checkpoint inhibitor therapy. Triple-negative breast cancer is characterized by higher tumor expression of the immunomodulatory protein programmed death ligand 1 (PD-L1), greater tumor mutational burden, and more extensive tumor-infiltrating lymphocytes than other breast cancer subtypes — all of which suggested potential benefit from immunotherapy. The survival data from the KEYNOTE-522 trial that are reported in this issue of the Journal are a major validation of that hypothesis.
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New England Journal of Medicine
The Duffy Null Phenotype - Addressing a Source of Discrimination in Cancer Care
Hantel A, Merz LE, Abel GA
Structural racism describes the barriers to equity built into myriad societal domains. It operates in health care by means of policies, practices, and systems, “affecting health in ways often more difficult to recognize than explicit interpersonal racism.” Efforts are under way to dismantle these mutually reinforcing structures in oncology. Cancer research and care practices that adversely affect people with the Duffy null phenotype, however, are an underrecognized and widespread source of discrimination against people of African or Arab ancestry.
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Proceedings of the National Academy of Sciences of the U.S.A.
PARG Inhibitor Sensitivity Correlates with Accumulation of Single-Stranded DNA Gaps in Preclinical Models of Ovarian Cancer
Ravindranathan R, Somuncu O, da Costa AABA, Mukkavalli S, Lamarre BP, Nguyen H, Grochala C, Jiao Y, Liu J, Kochupurakkal B, Parmar K, Shapiro GI, D'Andrea AD
Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair by removal of poly (ADP-ribose) (PAR) from PARylated proteins. Loss or inhibition of PARG results in replication stress and sensitizes cancer cells to DNA-damaging agents. PARG inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as cancer patients with germline or somatic BRCA1/2-mutations. PARP inhibitors kill BRCA-deficient cancer cells by increasing single-stranded DNA gaps (ssGAPs) during replication. Here, we report that, like PARP inhibitor (PARPi), PARG inhibitor (PARGi) treatment also causes an accumulation of ssGAPs in sensitive cells. PARGi exposure increased accumulation of S-phase-specific PAR, a marker for Okazaki fragment processing (OFP) defects on lagging strands and induced ssGAPs, in sensitive cells but not in resistant cells. PARGi also caused accumulation of PAR at the replication forks and at the ssDNA sites in sensitive cells. Additionally, PARGi exhibited monotherapy activity in specific HR-deficient, as well as HR-proficient, patient-derived, or patient-derived xenograft (PDX)-derived organoids of ovarian cancer, and drug sensitivity directly correlated with the accumulation of ssGAPs. Taken together, PARGi treatment results in toxic accumulation of PAR at replication forks resulting in ssGAPs due to OFP defects during replication. Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.
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Science
A Tetramer of BCL11A is Required for Stable Protein Production and Fetal Hemoglobin Silencing
Zheng G, Yin M, Mehta S, Chu IT, AlShaye A, Drainville K, Buyanbat A, Bienfait F, Tenglin K, Orkin SH
Down-regulation of BCL11A protein reverses the fetal (HbF, ?2?2) to adult (HbA, ?2?2) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for ?-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery.
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Cell Reports
ZBTB7A is a Modulator of KDM5-Driven Transcriptional Networks in Basal Breast Cancer
DiCiaccio B, Seehawer M, Li Z, Patmanidis A, Bui T, Foidart P, Nishida J, Papanastasiou M, Reiter AH, Qiu X, Li R, Jiang Y, Huang XY, Brown M, Long HW, Polyak K
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Circulation
Cardiovascular Complications and Their Association with Short- and Long-Term Outcomes in Patients with Multiple Myeloma and Lymphoma Undergoing Chimeric Antigen Receptor T-Cell Therapy
Itzhaki Ben Zadok O, Simitsis P, Jacobson C, Nadeem O, Frigault MJ, Raje N, Duffy C, Costello P, Dela Cruz J, Looka A, Nohria A
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Haematologica
Investigating the Influence of Germline ATM Variants in Chronic Lymphocytic Leukemia on Cancer Vulnerability
Azevedo RS, Morelli F, Mashima K, Fardoun R, Tyekucheva S, Fernandes S, Shupe S, Terra M, Patel A, Davids MS, Yu J, Brown JR
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Radiologia Medica
Quantification of Normal Bone and Osseous Metastases in Castration-Resistant Prostate Cancer Using SPECT/CT with xSPECT Quant: Prospective Imaging Sub-Study of a Phase 2 Clinical Trial Investigating the Combination of Pembrolizumab Plus Radium-223 Compared to Radium-223 Alone
Robertson MS, Wang Y, Cheng S, Park H, Glomski S, Harshman LC, Pace A, Kilar J, Flynn M, Gilbert L, Choudhury AD, Jacene H
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Science Advances
Genomic Heterogeneity and Ploidy Identify Patients with Intrinsic Resistance to PD-1 Blockade in Metastatic Melanoma
Tarantino G, Ricker CA, Wang A, Ge W, Aprati TJ, Huang AY, Madha S, Chen J, Shi Y, Glettig M, Frederick DT, Freeman S, Holovatska MM, Manos MP, Jameson JC, Saghafian S, Reardon B, Park J, Elmarakeby HA, Giobbie-Hurder A, Buchbinder EI, Flaherty KT, Haq R, Wu CJ, Boland GM, Hodi FS, Van Allen EM, Liu D
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