While leukemia is a cancer of the blood-forming system and is defined as the uncontrolled proliferation of bone marrow progenitor cells of either myeloid or lymphocytic origin, lymphomas also have a lymphoid origin, but arise outside the bone marrow, in the lymph nodes or other lymphatic tissues (e.g., tonsils, spleen) or from lymphoid cells in other organs or tissues. They are classified into two categories: Hodgkin and non-Hodgkin lymphomas (NHL). NHL is the 5th most common cancer and the number one hematological malignancy in the US. Our lymphoma studies strive to identify causal gene variants of NHL that may be used to identify at-risk individuals; expand our knowledge of the disease mechanisms involved in the cellular processes driving lymphomas; and provide important clues as to biological pathways/targets that may be amenable to therapeutic modulation.
In a recent meta-analysis of benzene exposure and NHL, findings of elevated risk provide evidence that benzene exposure is associated with an increased risk of NHL when results are adjusted for bias. We are also developing mass spectrometric methods to profile levels of protein adducts in serum from lymphoma patients and control subjects. By comparing adduct profiles between cases and controls, we hope to identify carcinogens associated with lymphoma.
Candidate Gene Studies
We recently identified a functional -1C>T SNP in the TNFRSF5 (CD40) gene that was associated with increased susceptibility to certain lymphomas, particularly follicular lymphoma in three independent studies. We also found that TT carriers exhibited reduced circulating soluble CD40 levels and dendritic cell CD40 expression.
These findings suggest that mechanisms that hinder cellular immune responses may be relevant to follicular lymphoma pathology.
We recently performed a genome wide association study (GWAS) of NHL that led to the identification of a number of potential NHL risk alleles (alternative DNA sequences at the same physical chromosomal location, which may or may not result in different traits). One of our top findings was the identification of a low-risk allele for follicular lymphoma in the C6orf15 (STG) gene located in the psoriasis susceptibility region 1 (PSORS1) on chromosome 6p21.33 (Skibola et al., Nature Genetics, 2009). In future studies, we will resequence this and other genomic regions associated with NHL to identify the true causal genetic variants for NHL. We are currently conducting validation studies within the international lymphoma consortium, InterLymph of findings from our second NHL GWAS study. This comprehensive study will define important genetic mechanisms in the etiology of lymphoma and associations described will likely yield clues to potentially important environmental factors. These studies will also allow us to gain a better understanding of the cellular processes underlying lymphomagenesis. We are also studying how interactions between environmental exposures and specific gene variants may influence NHL. These studies will provide relevant information to gain a more complete understanding of how common exposures and genetic variation may ultimately contribute to disease risk.
Amplified DNA Genotyping
Association studies designed to identify the genetic determinants underlying complex disease increasingly require sustainable high-quality DNA resources for large-scale single-nucleotide polymorphism (SNP) genotyping. Recent studies have shown that genomic DNA (gDNA) suitable for SNP genotyping can be obtained from buccal cells and from dried blood spots on Guthrie cards. We conclude that highly multiplexed Illumina genotyping may be done on gDNA and wgaDNA obtained from whole blood, buccal samples, dried blood spots on Guthrie cards, and possibly even urine samples, with minimal misclassification.
Skibola CF, Bracci PM, Halperin E, Conde L, Craig DW, Agana L, Iyadurai K, Becker N, Brooks-Wilson A, Curry JD, Spinelli JJ, Holly EA, Riby J, Zhang L, Nieters A, Smith MT, Brown KM (2009) Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nature Genet. Aug;41(8):873-5. PMID: 19620980. [Abstract] [Full Text]
Skibola CF, Nieters A, Bracci PM, Curry JD, Agana L, Skibola DR, Hubbard A, Becker N, Smith MT, Holly EA. (2008) A functional TNFRSF5 gene variant is associated with risk of lymphoma. Blood, 111(8):4348-54. PMID: 18287517. PMCID: PMC2288730 [Abstract] [Full Text]
Steinmaus CM, Smith AH, Jones RM, Smith MT (2008) Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association. Occup Environ Med, Jun;65(6):371-8. PMID: 18417556. [Abstract] [Full Text]
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