Dataset Information

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia.

ABSTRACT: Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR?=?21.14, 95% CI: 14.40-31.03, P?=?1.36?×?10-54) and 14q32.13 (rs117410836, near TCL1; OR?=?4.90, 95% CI: 3.45-6.96, P?=?8.75?×?10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

SUBMITTER: McMaster ML

PROVIDER: S-EPMC6180091 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

McMaster Mary L ML Berndt Sonja I SI Zhang Jianqing J Slager Susan L SL Li Shengchao Alfred SA Vajdic Claire M CM Smedby Karin E KE Yan Huihuang H Birmann Brenda M BM Brown Elizabeth E EE Smith Alex A Kleinstern Geffen G Fansler Mervin M MM Mayr Christine C Zhu Bin B Chung Charles C CC Park Ju-Hyun JH Burdette Laurie L Hicks Belynda D BD Hutchinson Amy A Teras Lauren R LR Adami Hans-Olov HO Bracci Paige M PM McKay James J Monnereau Alain A Link Brian K BK Vermeulen Roel C H RCH Ansell Stephen M SM Maria Ann A Diver W Ryan WR Melbye Mads M Ojesina Akinyemi I AI Kraft Peter P Boffetta Paolo P Clavel Jacqueline J Giovannucci Edward E Besson Caroline M CM Canzian Federico F Travis Ruth C RC Vineis Paolo P Weiderpass Elisabete E Montalvan Rebecca R Wang Zhaoming Z Yeager Meredith M Becker Nikolaus N Benavente Yolanda Y Brennan Paul P Foretova Lenka L Maynadie Marc M Nieters Alexandra A de Sanjose Silvia S Staines Anthony A Conde Lucia L Riby Jacques J Glimelius Bengt B Hjalgrim Henrik H Pradhan Nisha N Feldman Andrew L AL Novak Anne J AJ Lawrence Charles C Bassig Bryan A BA Lan Qing Q Zheng Tongzhang T North Kari E KE Tinker Lesley F LF Cozen Wendy W Severson Richard K RK Hofmann Jonathan N JN Zhang Yawei Y Jackson Rebecca D RD Morton Lindsay M LM Purdue Mark P MP Chatterjee Nilanjan N Offit Kenneth K Cerhan James R JR Chanock Stephen J SJ Rothman Nathaniel N Vijai Joseph J Goldin Lynn R LR Skibola Christine F CF Caporaso Neil E NE

Nature communications 20181010 1

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10<sup>-54</sup>) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10<sup> ...[more]

PMID: 30305637

Similar Datasets

Project description:Importance:Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system. Observations:Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant. Conclusions and Relevance:Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ?3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.

Dataset Information

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia.

Publications

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets