Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Johnson, David C.; Weinhold, Niels; Mitchell, Jonathan S.; Chen, Bowang; Kaiser, Martin; Begum, Dil; Hillengaß, Jens; Bertsch, Uta; Gregory, Walter A.; Cairns, David A.; Jackson, Graham; Försti, Asta; Nickel, Jolanta; Hoffmann, Per; Nöethen, Markus M.; Stephens, Owen; Barlogie, Bart; Davis, Faith E.; Hemminki, Kari; Goldschmidt, Hartmut; Houlston, Richard S.; Morgan, Gareth J.

doi:10.1038/ncomms10290

Cited by 29 publications

(27 citation statements)

References 59 publications

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“…Clinical trial information on these patients has been previously reported 47 48 49 50 . The primary analysis end point was myeloma-specific overall survival and analysis was performed as previously described 51 . Cox regression analysis was used to derive genotype-specific hazard ratio and associated 95% confidence intervals.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

et al. 2016

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Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

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Section: Methodsmentioning

confidence: 99%

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

et al. 2016

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“…In addition, the clinical relevance of most mutations has not yet been determined and is undergoing investigation in large sequencing programs (CoMMpass, The Myeloma Genome Project and others). 39 , 40 No mutation screening has yet been implemented in standard clinical workflows, but mutational analyses may help to identify potential therapeutic targets (such as BRAF mutations) and to stratify of patients in clinical trials.…”

Section: European Myeloma Network Recommendationsmentioning

confidence: 99%

European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when

et al. 2018

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The diagnosis of multiple myeloma can be challenging, even for experienced physicians, and requires close collaboration between numerous disciplines (orthopedics, radiology, nuclear medicine, radiation therapy, hematology and oncology) before the final diagnosis of myeloma is made. The definition of multiple myeloma is based on the presence of clinical, biochemical, histopathological, and radiological markers of disease. Specific tests are needed both at presentation and during follow-up in order to reach the correct diagnosis and characterize the disease precisely. These tests can also serve prognostic purposes and are useful for follow-up of myeloma patients. Molecular analyses remain pivotal for defining high-risk myeloma and are used in updated patient stratifications, while minimal residual disease assessment via flow cytometry, molecular techniques and radiological approaches provides additional prognostic information on patients’ long-term outcome. This pivotal information will guide our future treatment decisions in forthcoming clinical trials. The European Myeloma Network group updated their guidelines on different diagnostic recommendations, which should be of value to enable appropriate use of the recommendations both at diagnosis and during follow-up.

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“…P53, RB1, DIS3, CDKN2A and CDKN2C [193] , and mutations in members of the NF-κB pathway [194] and STAT3 [195] . The constitutional genotype of the tumor also plays a role in determining patient outcome [196] . Mutations in CDKN2A, a stabilizer of p53 increase sensitivity to chemotherapy [197] .…”

Section: Role Of Genetics and Genomics For Drug Resistancementioning

confidence: 99%

Drug targets and resistance mechanisms in multiple myeloma

Naß¹,

Efferth²

2018

CDR

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Multiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent blood cancer (10%). A PubMed search has been conducted for English research papers and reviews published until January 2018. Numerous drugs are used in treatment of MM. These include the antineoplastic alkylating agents cyclophosphamide, busulfan and melphalan, immunomodulators such as lenalidomide and thalidomide, corticosteroids including dexamethasone, microtubule-targeting agents, such as paclitaxel and vinca alkaloids, as well as the proteasome inhibitors bortezomib and carfilzomib. Despite the considerable number of treatment options, MM is still difficult to treat, which is mirrored by the poor 10-year survival rate of 3%. Resistance to chemotherapy is often the cause for therapy failure. These resistances can be due to the overexpression of efflux pumps, genetic and epigenetic aberrations and the microenvironment of MM. With the gain of knowledge regarding genetic and molecular changes, many molecular targeted therapies including cell signaling targeted therapies are being developed against relapsed/refractory MM. Additionally, epigenetic aberrations such as DNA methylation and histone modifications steered MM management in new directions. Amongst these novel targeted therapies, inhibitors of histone deacetylase, Aurora kinase, inhibitors of the PI3K/AKT/mTOR pathway and cyclin dependent kinases are promising.

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Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Cited by 29 publications

References 59 publications

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when

Drug targets and resistance mechanisms in multiple myeloma

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