Although there are advances in understanding the pathogenesis of multiple myeloma, its causes remain elusive. Risk is increased by 1.5-3-fold in family members of cases, suggesting a genetic contribution. It is possible that plasma cell growth factors and proteins important in B cell differentiation may contribute to risk by increasing the pool of plasma cells available for transformation to myeloma. In prior SPORE supported pilot studies, we found evidence linking polymorphisms (i.e., """"""""SNP""""""""s) in genes that control two important plasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility to multiple myeloma. In addition, we found positive associations between polymorphisms of certain DNA repair genes and multiple myeloma risk. These studies had strong prior hypotheses but small sample sizes, and thus the possibility of false positive results is a. concern. Furthermore, since multiple myeloma disproportionately affects African-Americans and Hispanics (to a lesser degree), it is important to conduct studies in a multi-ethnic setting, whereas the pilot studies included relatively few ethnic minorities. Therefore we propose to confirm these preliminary findings in a larger multi-ethnic sample of 559 cases and 885 controls from 5 separate studies with existing DNA samples, including the Health Professionals Follow-up Study, Nurse's Health Study, and the USC-Hawaii Multi-ethnic Cohort Study, and two population-based case-control studies. We will include several genes in plasma cell growth and B cell differentiation pathways. In choosing the SNPs to examine in this study, we will take into account the ethnic diversity of the participating study populations, as well as considerations related to the structure of the genes of interest. We have developed a powerful software program to choose polymorphisms based on those considerations from HapMap, and we will genotype 1,536 SNPs in 25 genes using well-validated, efficient genotyping technology through the DSC Genotyping Core Facility. We will examine the association of variation in individual genes with myeloma risk, accounting for correlations between SNPs. We will also interact with other SPORE projects to interrogate the function of any SNPs that we observe to be associated with risk. We believe this project enhances the overall value of the SPORE by contributing to the understanding of genetic susceptibility to multiple myeloma, needed for the development of both treatment and prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA100707-10
Application #
8382447
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$292,820
Indirect Cost
$81,081
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, L; Tai, Y-T; Ho, M et al. (2017) Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J 7:e547
Jain, Salvia; Washington, Abigail; Leaf, Rebecca Karp et al. (2017) Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma. Mol Cancer Ther 16:2304-2314
Gullà, A; Hideshima, T; Bianchi, G et al. (2017) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia :
Harada, T; Ohguchi, H; Grondin, Y et al. (2017) HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31:2670-2677
Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika et al. (2017) Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma. Br J Haematol 179:756-771
Bouillez, A; Rajabi, H; Jin, C et al. (2017) MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene 36:4037-4046
Das, Deepika Sharma; Das, Abhishek; Ray, Arghya et al. (2017) Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells. Clin Cancer Res 23:4280-4289
Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan et al. (2017) Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma. Oncotarget 8:69237-69249
Ray, A; Das, D S; Song, Y et al. (2017) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia :
Song, Y; Li, S; Ray, A et al. (2017) Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 36:5631-5638

Showing the most recent 10 out of 388 publications