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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

ABSTRACT: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL.GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis.Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765.These data suggest several plausible genetic links between DLBCL and SLE.

SUBMITTER: Bernatsky S

PROVIDER: S-EPMC5715504 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

Bernatsky Sasha S Velásquez García Héctor A HA Spinelli John J JJ Gaffney Patrick P Smedby Karin E KE Ramsey-Goldman Rosalind R Wang Sophia S SS Adami Hans-Olov HO Albanes Demetrius D Angelucci Emanuele E Ansell Stephen M SM Asmann Yan W YW Becker Nikolaus N Benavente Yolanda Y Berndt Sonja I SI Bertrand Kimberly A KA Birmann Brenda M BM Boeing Heiner H Boffetta Paolo P Bracci Paige M PM Brennan Paul P Brooks-Wilson Angela R AR Cerhan James R JR Chanock Stephen J SJ Clavel Jacqueline J Conde Lucia L Cotenbader Karen H KH Cox David G DG Cozen Wendy W Crouch Simon S De Roos Anneclaire J AJ de Sanjose Silvia S Di Lollo Simonetta S Diver W Ryan WR Dogan Ahmet A Foretova Lenka L Ghesquières Hervé H Giles Graham G GG Glimelius Bengt B Habermann Thomas M TM Haioun Corinne C Hartge Patricia P Hjalgrim Henrik H Holford Theodore R TR Holly Elizabeth A EA Jackson Rebecca D RD Kaaks Rudolph R Kane Eleanor E Kelly Rachel S RS Klein Robert J RJ Kraft Peter P Kricker Anne A Lan Qing Q Lawrence Charles C Liebow Mark M Lightfoot Tracy T Link Brian K BK Maynadie Marc M McKay James J Melbye Mads M Molina Thierry J TJ Monnereau Alain A Morton Lindsay M LM Nieters Alexandra A North Kari E KE Novak Anne J AJ Offit Kenneth K Purdue Mark P MP Rais Marco M Riby Jacques J Roman Eve E Rothman Nathaniel N Salles Gilles G Severi Gianluca G Severson Richard K RK Skibola Christine F CF Slager Susan L SL Smith Alex A Smith Martyn T MT Southey Melissa C MC Staines Anthony A Teras Lauren R LR Thompson Carrie A CA Tilly Hervé H Tinker Lesley F LF Tjonneland Anne A Turner Jenny J Vajdic Claire M CM Vermeulen Roel C H RCH Vijai Joseph J Vineis Paolo P Virtamo Jarmo J Wang Zhaoming Z Weinstein Stephanie S Witzig Thomas E TE Zelenetz Andrew A Zeleniuch-Jacquotte Anne A Zhang Yawei Y Zheng Tongzhang T Zucca Mariagrazia M Clarke Ann E AE

Lupus science & medicine 20171112 1

<h4>Objective</h4>Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL.<h4>Methods</h4>GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data wer ...[more]

PMID: 29214033

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Project description:BackgroundPatients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway.Materials and methodsWe evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features.ResultsThe majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive for pPTEN was positively correlated with p70S6K levels (p = 0.016 for 235/236 and p = 0.007 for 240/244). High levels of pPRAS40 were observed in the majority of the cases evaluated (64.3%), but no correlation was found with either pPTEN (p = 0.9) or p70S6K (p = 0.9) levels.ConclusionAR-DLBCL frequently contain p70S6K, a main downstream effector of the mTOR pathway. The presence of p70S6K is positively correlated with pPTEN, an inactive form of PTEN, which makes mTORC1 activated. The presence of p70S6K was independent of HIV viral load or CD4 (+) counts. These results suggest that the mTOR pathway is active in the majority of AR-DLBCL, and p70S6K, particularly the Ser240/244 epitope immunohistochemistry is an excellent surrogate biomarker, which could be used to identify cases expected to be responsive to mTOR inhibitors.

Project description:Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma with an increased tendency to relapse or refractoriness. RAB39B, a member of the Ras-oncogene superfamily, is associated with a variety of tumors. Nevertheless, the role of RAB39B in DLBCL is still unknown. This study aimed to identify the role of RAB39B in DLBCL using integrated bioinformatics analysis. Methods: RAB39B expression data were examined using TIMER, UCSC, and GEO databases. The LinkedOmics database was used to study the genes and signaling pathways related to RAB39B expression. A Protein-protein interaction network was performed in STRING. TIMER was used to analyze the correlation between RAB39B and infiltrating immune cells. The correlation between RAB39B and m6A-related genes in DLBCL was analyzed using TCGA data. The RAB39B ceRNA network was constructed based on starBase and miRNet2.0 databases. Drug sensitivity information was obtained from the GSCA database. Results: RAB39B was highly expressed in multiple tumors including DLBCL. The protein-protein interaction network showed enrichment of autophagy and RAS family proteins. Functional enrichment analysis of RAB39B co-expression genes revealed that RAB39B was closely related to DNA replication, protein synthesis, cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, NF-kappa B signaling pathway, and autophagy. Immune infiltrate analysis showed that the amount of RAB39B was negatively correlated with iDC, Tem, and CD8 T-cell infiltration. CD4+ T cell and DC were negatively correlated with CNV of RAB39B. DLBCL cohort analysis found that RAB39B expression was related to 14 m6A modifier genes, including YTHDC1, YTHDC2, YTHDF1, YTHDF2, YTHDF3, RBMX, ZC3H13, METTL14, METTL3, RBM15, RBM15B, VIRMA, FTO, and ALKBH5. We constructed 14 possible ceRNA networks of RAB39B in DLBCL. The RAB39B expression was associated with decreased sensitivity of chemotherapy drugs such as dexamethasone, doxorubicin, etoposide, vincristine, and cytarabine and poor overall survival in DLBCL. In vitro experiments showed that RAB39B was associated with proliferation, apoptosis, and drug sensitivity of DLBCL cells. Conclusion: RAB39B is abnormally elevated and related to drug resistance and poor OS in DLBCL, which may be due to its involvement in immune infiltration, m6A modification, and regulation by multiple non-coding RNAs. RAB39B may be used as an effective biomarker for the diagnosis and treatment of DLBCL.

Dataset Information

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

Publications

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

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