Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s lymphoma

Frampton, Matthew; Filho, Miguel Inácio da Silva; Broderick, Peter; Thomsen, Hauke; Försti, Asta; Vijayakrishnan, Jayaram; Cooke, Rosie; Enciso-Mora, Victor; Hoffmann, Per; Nöthen, Markus M.; Lloyd, Amy; Holroyd, Amy; Eisele, Lewin; Jöckel, Karl Heinz; Ponader, Sabine; Strandmann, Elke Pogge von; Lightfoot, Tracy; Roman, Eve; Lake, Annette; Montgomery, Dorothy; Jarrett, Ruth F.; Swerdlow, Anthony; Engert, Andreas; Hemminki, Kari; Houlston, Richard S.

doi:10.1038/ncomms3549

Cited by 61 publications

(84 citation statements)

References 40 publications

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“…A detailed overview of the study material, the identification of samples of non-European origin, the plots of the principal components and the results is given in our previous paper. 6 The genome-wide Armitage trend test χ2 values showed minimal inflation of the test statistics proving the absence of substantial cryptic population substructure (genomic control inflation factor λ gc = 1.09). 6 By using PLINK software 18 we finally produced two subsets of data with SNPs in cases and controls that had either a minor allele frequency (MAF) of 40.01 or MAF of 40.05.…”

Section: Genomic Data: Quality Control Of Snp Genotypingmentioning

confidence: 99%

“…Although the genomic control inflation factor was still small and mainly influenced by the distribution of cases collected across Germany, 6 genomic partitioning was used to check the final influence of the population structure. 20,32 Estimates were derived for chromosomes 1-7 and for the remaining chromosomes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Estimates Of the Variance Explained By Snpsmentioning

confidence: 99%

“…5 Recently, several genome-wide association studies (GWASs) have identified a couple of loci for HL. 6,7 These studies have shown that the risk of HL is highly influenced by the human leukocyte antigen (HLA) genotype variation, but the familial risk is also a consequence of non-HLA genotype variation. 6 However, all the genetic variants identified so far only capture a minor percentage of the estimated heritability of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 These studies have shown that the risk of HL is highly influenced by the human leukocyte antigen (HLA) genotype variation, but the familial risk is also a consequence of non-HLA genotype variation. 6 However, all the genetic variants identified so far only capture a minor percentage of the estimated heritability of the disease. 8 Yet, a great deal remains to be understood regarding the remaining heritability.…”

Section: Introductionmentioning

confidence: 99%

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Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

et al. 2014

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Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of Hodgkin's lymphoma (HL) and demonstrated the association of common genetic variation for this type of cancer. Such evidence for inherited genetic risk is also provided by the family history and the very high concordance between monozygotic twins. However, little is known about the genetic and environmental contributions. A common measure for describing the phenotypic variation due to genetics is the heritability. Using GWAS data on 906 HL cases by considering all typed SNPs simultaneously, we have calculated that the common variance explained by SNPs accounts for 435% of the total variation on the liability scale in HL (95% confidence interval 6-62%). These findings are consistent with similar heritability estimates of ∼ 0.40 (95% confidence interval 0.17-0.58) based on Swedish population data. Our estimates support the underlying polygenic basis for susceptibility to HL, and show that heritability based on the population data is somehow larger than heritability based on the genomic data because of the possibility of some missing heritability in the GWAS data. Besides that there is still major evidence for multiple loci causing HL on chromosomes other than chromosome 6 that need to be detected. Because of limited findings in prior GWASs, it seems worth checking for more loci causing susceptibility to HL.

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Section: Genomic Data: Quality Control Of Snp Genotypingmentioning

confidence: 99%

Section: Estimates Of the Variance Explained By Snpsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

et al. 2014

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“…[10][11][12] Other non-HLA susceptibility loci have been identified through GWAS. [13][14][15] The identification of genes with major susceptibility effects has been more difficult. A study of a family with a reciprocal translocation between chromosomes 2 and 3 segregating with HL led to the identification of a disruption in the gene KLDHC8B, which codes for a midbody kelch protein, hypothesized to disrupt cytokinesis thereby promoting tumorigenesis.…”

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confidence: 99%

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

et al. 2016

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H odgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.

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Association of Single-Nucleotide Variants in the Human Leukocyte Antigen and Other Loci With Childhood Hodgkin Lymphoma

et al. 2022

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IMPORTANCEStudies focusing on genetic susceptibility of childhood Hodgkin lymphoma (HL) are limited. OBJECTIVES To identify genetic variants associated with childhood-onset HL vs adult-onset HL. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was performed with 3 cohorts: the St Jude Lifetime Cohort Study (SJLIFE), initiated in 2007 with ongoing follow-up, and the original and expansion cohorts of the Childhood Cancer Survivor Study (CCSS), initiated in the 1990s with ongoing follow-up. Results of these genome-wide association studies (GWASs) were combined via meta-analysis. Data were analyzed from June 2021 to June 2022. MAIN OUTCOMES AND MEASURES Childhood HL was the focused outcome. Single-nucleotide variant (SNV, formerly single-nucleotide polymorphism) array genotyping and imputation were conducted for the CCSS original cohort, and whole-genome sequencing was performed for the SJLIFE and CCSS expansion cohort.RESULTS A total of 1286 HL cases (mean diagnosis [SD] age, 14.6 [3.9] years), 6193 non-HL childhood cancer cases, and 369 noncancer controls, all of European ancestry, were included in the analysis. Using step-wise conditional logistic regression, the odds ratios (ORs) for each of the 3 independent SNVs identified in the human leukocyte antigen (HLA) locus were 1.80 (95% CI, 1.59-2.03;

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Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s lymphoma

Cited by 61 publications

References 40 publications

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

Association of Single-Nucleotide Variants in the Human Leukocyte Antigen and Other Loci With Childhood Hodgkin Lymphoma

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