Variation in innate immunity genes and risk of multiple myeloma

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/DHHS, Bethesda, MD, USA.
Hematological Oncology (Impact Factor: 3.08). 03/2011; 29(1):42-6. DOI: 10.1002/hon.954
Source: PubMed


Multiple myeloma (MM) is a B-cell lymphoid malignancy suspected to be associated with immunologic factors. Given recent findings associating single-nucleotide polymorphisms (SNPs) in innate immunity genes with non-Hodgkin lymphoma, we conducted an investigation of innate immune gene variants using specimens from a population-based case-control study of MM conducted in Connecticut women. Tag SNPs (N = 1461) summarizing common variation in 149 gene regions were genotyped in non-Hispanic Caucasian subjects (103 cases, 475 controls). Odds ratios (OR) and 95% confidence intervals (CI) relating SNP associations with MM were computed using unconditional logistic regression, while the MinP test was used to investigate associations with MM at the gene level. We calculated permutation-adjusted P-values and false discovery rates (FDR) to account for the number of comparisons performed in SNP-level and gene-level tests, respectively. Three genes were associated with MM when controlling for a FDR of ≤10%: SERPINE1 (P(MinP)  < 0.0001; FDR = 0.02), CCR7 (P(MinP)  = 0.0006; FDR = 0.06) and HGF (P(MinP)  = 0.001; FDR = 0.08). Two SNPs demonstrated robust associations: SERPINE1 rs2227667 (P = 2.1 × 10(-5) , P(permutation)  = 0.03) and HGF rs17501108 (P = 5.0 × 10(-5) , P(permutation)  = 0.07). Our findings suggest that genetic variants in SERPINE1 and HGF, and possibly CCR7, are associated with MM risk, and warrant further investigation in other studies.

Download full-text


Available from: Idan Menashe
  • Source
    • "The CCL5 -403A allele conferred an increased risk of prostate, oral and pancreatic cancer [18,22,23]. Furthermore, inheritance of the CCR7 rs3136685 AG+AA or CCR7 rs3136687 (AG, AG+AA) genotypes was associated with a 60-62% reduction in multiple myeloma (MM) and chronic lymphocytic leukemia, respectively [19,21]. Unfortunately, these previously mentioned studies focused on single SNPs in relation to cancer primarily among men of European descent. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.
    Full-text · Article · Nov 2012 · Hereditary Cancer in Clinical Practice
  • Source
    • "The processing of single-chain HGF was significantly enhanced by the addition of thrombin and was completely inhibited by serine protease inhibitors, such as aprotinin. Interestingly, single nucleotide polymorphisms of the HGF gene have been associated with myeloma risk [65]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome.
    Full-text · Article · Apr 2012 · Clinical and Developmental Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Malignancies of the lymphoid cells, including non-Hodgkin lymphomas (NHL), HL, and multiple myeloma, occur at much lower rates in Asians than other racial/ethnic groups in the United States. It remains unclear whether these deficits are explained by genetic or environmental factors. To better understand environmental contributions, we examined incidence patterns of lymphoid malignancies among populations characterized by ethnicity, birthplace, and residential neighborhood socioeconomic status (SES) and ethnic enclave status. We obtained data about all Asian patients diagnosed with lymphoid malignancies between 1988 and 2004 from the California Cancer Registry and neighborhood characteristics from U.S. Census data. Although incidence rates of most lymphoid malignancies were lower among Asian than white populations, only follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and nodular sclerosis (NS) HL rates were statistically significantly lower among foreign-born than U.S.-born Asians with incidence rate ratios ranging from 0.34 to 0.87. Rates of CLL/SLL and NS HL were also lower among Asian women living in ethnic enclaves or lower SES neighborhoods than those living elsewhere. These observations support strong roles of environmental factors in the causation of FL, CLL/SLL, and NS HL. Studying specific lymphoid malignancies in U.S. Asians may provide valuable insight toward understanding their environmental causes.
    Full-text · Article · Jun 2011 · Cancer Epidemiology Biomarkers & Prevention
Show more