Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies

Autor: Carol S. Portlock, Robert J. Klein, Nichole Hansen, Kenneth Offit, Agnes Viale, Ana Dutra-Clarke, Mark E. Robson, Liying Zhang, Sohela Shah, Rohini Rau-Murthy, Jennifer A. Przybylo, Jennifer R. Brown, Christopher Manschreck, Joseph Vijai, Kasmintan A. Schrader, Tomas Kirchhoff, Kara Sarrel, Dina Ben-Yehuda, Zsofia K. Stadler, Srujana Cheguri, Ora Paltiel, Steven M. Lipkin, David J. Straus, Andrew D. Zelenetz, Mortimer J. Lacher
Rok vydání: 2013
Předmět:
Cancer Research
Candidate gene
Follicular lymphoma
Gene Expression
Genome-wide association study
0302 clinical medicine
Lymphoma
Follicular
Genetics (clinical)
Genetics
0303 health sciences
Genomics
Genome Scans
3. Good health
030220 oncology & carcinogenesis
Allelic heterogeneity
Research Article
lcsh:QH426-470
Quantitative Trait Loci
Single-nucleotide polymorphism
Human leukocyte antigen
Biology
Polymorphism
Single Nucleotide
03 medical and health sciences
Genome Analysis Tools
Cell Line
Tumor
Cancer Genetics
Genome-Wide Association Studies
Genetic predisposition
medicine
Humans
Genetic Predisposition to Disease
Trait Locus Analysis
Molecular Biology
Alleles
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Population Biology
Chromosomes
Human
Pair 11
Human Genetics
medicine.disease
Leukemia
Lymphoid
Lymphoma
lcsh:Genetics
Genetics of Disease
Immunology
Genetic Polymorphism
Population Genetics
Genome-Wide Association Study
Zdroj: PLoS Genetics
PLoS Genetics, Vol 9, Iss 1, p e1003220 (2013)
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1003220
Popis: The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Author Summary B-cell lymphomas comprise several diseases representing aberrant proliferations of immune cells at various stages of maturation. It might be expected that dissimilar subtypes of lymphoma will have different etiologic and pathogenic mechanisms, reflecting the distinct histologic and clinical characteristics of these diseases. This study aims to define both shared as well as specific genetic risk factors for lymphoma. Utilizing a genome-wide approach, we discovered novel locations in the genome associated with risk for lymphoid malignancies. Common variants in these regions, on chromosome 11q12.1 and 6p23, were each associated with a modest modification of risk for lymphoma. These regions harbor several genes of biological importance in lymphoid maturation and function. We also further characterized the HLA region at 6p21.32, previously associated with lymphoma risk and thought to be important in immune function. Some of the associated SNP markers were specific for one common subtype of lymphoma, e.g. follicular lymphoma. However, others were associated with combined subsets of disease, suggesting that there are both shared and subtype-specific associations between common genetic variants and human lymphoid cancer. Secondary analyses showed that the two novel regions harbor candidates that are biologically relevant and that regulate cell development and hematopoiesis.
Databáze: OpenAIRE
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