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Myeloma genomics

Charlotte Cosemans, Bénedith Oben, Ingrid Arijs, Annick Daniëls, Jeroen Declercq, Kimberly Vanhees, Guy Froyen, Brigitte Maes, Jeroen Mebis, Jean-Luc Rummens
Multiple myeloma (MM), characterized by malignant plasma cells in the bone marrow, is consistently preceded by asymptomatic premalignant stage monoclonal gammopathy of undetermined significance (MGUS). These MGUS patients have an annual risk of 1% to progress to MM. Clinical, imaging, and genomic (genetic and epigenetic) factors were identified, whose presence increased the risk of progression from MGUS to MM. In this systematic review we summarize the currently identified clinical, imaging, and genomic biomarkers suggested to increase the progression risk or shown to be differentially expressed/present between both cohorts of patients...
February 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
Charlotte Pawlyn, Andrea Loehr, Cody Ashby, Ruslana Tytarenko, Shayu Deshpande, James Sun, Kyle Fedorchak, Tariq Mughal, Faith E Davies, Brian A Walker, Gareth J Morgan
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...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jonathon H Gralewski, Ginell R Post, Frits van Rhee, Youzhong Yuan
BACKGROUND: Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. CASE PRESENTATION: A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant...
February 20, 2018: Diagnostic Pathology
Gerard Nuovo, Hue Tran, Andres Gutierrez, Paolo Fadda, Flavia Pichiorri, Enrico Caserta, Craig C Hofmeister, Marta Chesi, P Leif Bergsagel, Don Morris, Qiao Shi, Matt Coffey, Chandini Thirukkumaran
Acute reoviral infection has been extensively studied given the virus's propensity to target malignant cells and activate caspase-3 mediated apoptosis. Reovirus infection of malignant N1E-115 mouse neuroblastoma cells led to significant increased expression of importin-β and exportin-5 mRNAs (qRTPCR) and proteins (immunohistochemistry) which was partially blocked by small interfering LNA oligomers directed against the reoviral genome. Co-expression analysis showed that the N1E-115 cells that contained reoviral capsid protein had accumulated importin-β and exportin-5, as well as activated caspase 3...
February 2018: Annals of Diagnostic Pathology
Rosalie G Waller, Todd M Darlington, Xiaomu Wei, Michael J Madsen, Alun Thomas, Karen Curtin, Hilary Coon, Venkatesh Rajamanickam, Justin Musinsky, David Jayabalan, Djordje Atanackovic, S Vincent Rajkumar, Shaji Kumar, Susan Slager, Mridu Middha, Perrine Galia, Delphine Demangel, Mohamed Salama, Vijai Joseph, James McKay, Kenneth Offit, Robert J Klein, Steven M Lipkin, Charles Dumontet, Celine M Vachon, Nicola J Camp
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs...
February 2018: PLoS Genetics
Lucia Nobili, Domenica Ronchetti, Luca Agnelli, Elisa Taiana, Cristina Vinci, Antonino Neri
Multiple myeloma (MM) is an incurable disease caused by the malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Although a large fraction of the genome is actively transcribed, most of the transcripts do not serve as templates for proteins and are referred to as non-coding RNAs (ncRNAs), broadly divided into short and long transcripts on the basis of a 200-nucleotide threshold. Short ncRNAs, especially microRNAs, have crucial roles in virtually all types of cancer, including MM, and have gained importance in cancer diagnosis and prognosis, predicting the response to therapy and, notably, as innovative therapeutic targets...
February 1, 2018: Genes
Jan Smetana, Jan Oppelt, Martin Štork, Luděk Pour, Petr Kuglík
Background: Catastrophic chromosomal event known as chromothripsis was proven to be a significant hallmark of poor prognosis in several cancer diseases. While this phenomenon is very rare in among multiple myeloma (MM) patients, its presence in karyotype is associated with very poor prognosis. Case presentation: In our case, we report a 62 year female patient with rapid progression of multiple myeloma (MM) into extramedullary disease and short overall survival (OS = 23 months)...
2018: Molecular Cytogenetics
Nalinikanth Kotagiri, Matthew L Cooper, Michael Rettig, Christopher Egbulefu, Julie Prior, Grace Cui, Partha Karmakar, Mingzhou Zhou, Xiaoxia Yang, Gail Sudlow, Lynne Marsala, Chantiya Chanswangphuwana, Lan Lu, LeMoyne Habimana-Griffin, Monica Shokeen, Xinming Xu, Katherine Weilbaecher, Michael Tomasson, Gregory Lanza, John F DiPersio, Samuel Achilefu
Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells...
January 18, 2018: Nature Communications
Szymon Andrzej Zmorzynski, Iwona Korszen-Pilecka, Magdalena Wojcierowska-Litwin, Barbara Kwiatkowska-Drabik, Malgorzata Luterek, Sylwia Chocholska, Dorota Koczkodaj, Sylwia Popek, Malgorzata Michalak-Wojnowska, Grazyna Swiderska-Kolacz, Joanna Januszewska, Iwona Surowiec, Waldemar Tomczak, Marek Hus, Anna Dmoszynska, Marcin Pasiarski, Katarzyna Poniewierska-Jasak, Katarzyna Cieplinska, Olga Jankowska-Lecka, Agata Anna Filip
INTRODUCTION: Significant and accessible predictive factors for bortezomib treatment in plasma cell myeloma (PCM) are still lacking. TP53 codon 72 polymorphism (P72R) results in proline (P) or arginine (R) at 72 amino acid position, which causes synthesis of proteins with distinct functions. The aims of our study were to: 1) analyze whether this polymorphism is associated with an increased risk of PCM; 2) study whether the P72R polymorphism affects overall survival (OS) among PCM patients; 3) assess the possible association of the P72R polymorphism with sensitivity to bortezomib in cell cultures derived from PCM patients...
January 15, 2018: Folia Histochemica et Cytobiologica
Daniela Belloni, Silvia Heltai, Maurilio Ponzoni, Antonello Villa, Barbara Vergani, Lorenza Pecciarini, Magda Marcatti, Stefania Girlanda, Giovanni Tonon, Fabio Ciceri, Federico Caligaris-Cappio, Marina Ferrarini, Elisabetta Ferrero
Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells...
January 11, 2018: Haematologica
Vijay Ramakrishnan, Shaji Kumar
Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most common hematological malignancy. The disease is characterized by the accumulation of abnormal plasma cells in the bone marrow that remains in close association with other cells in the marrow microenvironment. In addition to the genomic alterations that commonly occur in MM, the interaction with cells in the marrow microenvironment promotes signaling events within the myeloma cells that enhances survival of MM cells...
January 11, 2018: Leukemia & Lymphoma
Taiga Nishihori, Kenneth Shain
Although recent advances in novel treatment approaches and therapeutics have shifted the treatment landscape of multiple myeloma, it remains an incurable plasma cell malignancy. Growing knowledge of the genome and expressed genomic information characterizing the biologic behavior of multiple myeloma continues to accumulate. However, translation and incorporation of vast molecular understanding of complex tumor biology to deliver personalized and precision treatment to cure multiple myeloma have not been successful to date...
2017: International Journal of Genomics
N Bolli, G Biancon, M Moarii, S Gimondi, Y Li, C de Philippis, F Maura, V Sathiaseelan, Y-T Tai, L Mudie, S O'Meara, K Raine, J W Teague, A P Butler, C Carniti, M Gerstung, T Bagratuni, E Kastritis, M Dimopoulos, P Corradini, K Anderson, P Moreau, S Minvielle, P J Campbell, E Papaemmanuil, H Avet-Loiseau, N C Munshi
In multiple myeloma, next generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here, we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number changes (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case. Known and novel independent prognostic markers were identified in our cohort of proteasome inhibitor and IMiD-treated patients with long follow-up, including events with context-specific prognostic value, such as deletions of the PRDM1 gene...
December 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Elisa Lazzari, Phoebe K Mondala, Nathaniel Delos Santos, Amber C Miller, Gabriel Pineda, Qingfei Jiang, Heather Leu, Shawn A Ali, Anusha-Preethi Ganesan, Christina N Wu, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, A Keith Stewart, Leslie A Crews, Catriona H M Jamieson
Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set...
December 4, 2017: Nature Communications
Pengze Wu, Tingting Li, Ruifeng Li, Lumeng Jia, Ping Zhu, Yifang Liu, Qing Chen, Daiwei Tang, Yuezhou Yu, Cheng Li
The Hi-C method is widely used to study the functional roles of the three-dimensional (3D) architecture of genomes. Here, we integrate Hi-C, whole-genome sequencing (WGS) and RNA-seq to study the 3D genome architecture of multiple myeloma (MM) and how it associates with genomic variation and gene expression. Our results show that Hi-C interaction matrices are biased by copy number variations (CNVs) and can be used to detect CNVs. Also, combining Hi-C and WGS data can improve the detection of translocations...
December 5, 2017: Nature Communications
A Cleynen, R Szalat, M Kemal Samur, S Robiou du Pont, L Buisson, E Boyle, M L Chretien, K Anderson, S Minvielle, P Moreau, M Attal, G Parmigiani, J Corre, N Munshi, H Avet-Loiseau
Multiple myeloma is a plasma cell malignancy characterized by recurrent IgH translocations and well described genomic heterogeneity. Although transcriptome profiles in multiple myeloma has been described, landscape of expressed fusion genes and their clinical impact remains unknown. To provide a comprehensive and detailed fusion gene cartography and suggest new mechanisms of tumorigenesis in multiple myeloma, we performed RNA sequencing in a cohort of 255 newly diagnosed and homogeneously treated multiple myeloma patients with long follow-up...
December 1, 2017: Nature Communications
Suchada Sommaluan, Budsaba Rerkamnuaychoke, Teeraya Pauwilai, Suporn Chancharunee, Preeyaporn Onsod, Pitichai Pornsarayuth, Takol Chareonsirisuthigul, Rachaneekorn Tammachote, Teerapong Siriboonpiputtana
Multiple myeloma (MM) is a hematological malignancy characterized by abnormal accumulation of clonal plasma cells in the bone marrow. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for detection of common genetic alterations in MM patients. Here, we aimed to confirm MLPA utility for this purpose and furthermore to test the feasibility of a combination of karyotyping, interphase fluorescence in situ hybridization (iFISH) and MLPA methods for diagnosis, prognostic assessment and risk stratification of MM...
November 26, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
Zarko Manojlovic, Austin Christofferson, Winnie S Liang, Jessica Aldrich, Megan Washington, Shukmei Wong, Daniel Rohrer, Scott Jewell, Rick A Kittles, Mary Derome, Daniel Auclair, David Wesley Craig, Jonathan Keats, John D Carpten
Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups...
November 2017: PLoS Genetics
C Botta, M Cucè, M R Pitari, D Caracciolo, A Gullà, E Morelli, C Riillo, L Biamonte, M E G Cantafio, R Prabhala, C Mignogna, A Di Vito, E Altomare, N Amodio, M T Di Martino, P Correale, M Rossi, A Giordano, N C Munshi, P Tagliaferri, P Tassone
Dendritic cells (DCs) play a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their miRNA network. By analyzing 6 different miRNA-profiling datasets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients...
November 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nadine K Berry, Amanda Dixon-McIver, Rodney J Scott, Philip Rowlings, Anoop K Enjeti
Plasma cell disorders (PCD) range from benign to highly malignant disease. The ability to detect risk-stratifying aberrations based on cytogenetic and molecular genetic assays plays an increasing role in therapeutic decision making. In this study, 58 patients were chosen for screening by comparative genomic hybridisation microarray (aCGH) to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis. All patients had an unequivocal clinical diagnosis of a plasma cell disorder (plasma cell myeloma (PCM)(n = 51) or monoclonal gammopathy of undetermined significance (MGUS)(n = 7)) and an abnormal FISH result...
December 2017: Cancer Genetics
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