Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms

Kushekhar, Kushi; Berg, Anke van den; Nolte, Ilja M.; Hepkema, Bouke; Visser, Lydia; Diepstra, Arjan

doi:10.1158/1055-9965.epi-14-0683

Cited by 49 publications

(33 citation statements)

References 72 publications

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“…Linkage studies in HL have identified both HLA class I (for Epstein-Barr virus [EBV]1) and class II (for EBV2) risk, and protective alleles and haplotypes. 10,11 Beyond HLA, linkage studies in CLL, 38 HL, 39 and WM 40 have not definitively identified genes with large effects, and there are no published studies in FL, DLBCL, or other NHL subtypes. For CLL, significant linkage was identified at 2q21.2, which contains the chemokine receptor (CXCR4) gene and for which rare coding mutations have been identified.…”

Section: Linkage Studiesmentioning

confidence: 99%

“…Also, the International Haplotype Map 46 and later the 1000 Genomes 47 projects, which catalog human genetic variation, became available as a reference and allowed "tagging" of genes and gene regions to take advantage of linkage disequilibrium (LD) to efficiently cover all of the common genetic variations for more comprehensive genotyping studies. 43 Although many studies of candidate genes have been published [7][8][9]11,48 , most findings have failed to replicate likely due to study design, bias from population stratification (ie, confounding by race or ethnicity), small sample size (low power), uncontrolled multiple testing (leading to false-positive associations), and unrealistic expectations in our ability to choose variants and genes. 49 The most robust findings have been for an LTA-TNF haplotype with DLBCL (P 5 2.93 3 10 ; and certain HLA alleles in class I (including HLA-A*01 and *02) with EBV1 HL and class II (including HLA-DRB1) with EBV2 HL.…”

Section: Genetic Association Studiesmentioning

confidence: 99%

“…49 The most robust findings have been for an LTA-TNF haplotype with DLBCL (P 5 2.93 3 10 ; and certain HLA alleles in class I (including HLA-A*01 and *02) with EBV1 HL and class II (including HLA-DRB1) with EBV2 HL. 11 …”

Section: Genetic Association Studiesmentioning

confidence: 99%

“…Building from prior reviews, [5][6][7][8][9][10][11] we focus on the strongest data addressing familial predisposition (including twin, case-control, and registry-based studies) and germline susceptibility loci (including linkage and genetic-association studies) for lymphoma, and put these findings into clinical context. One emerging theme on the etiology of lymphoma is that there is both commonality and heterogeneity for risk factors by subtype, 12 and thus we consider this issue as well in the context of familial predisposition and genetic risk factors.…”

Section: Introductionmentioning

confidence: 99%

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Familial predisposition and genetic risk factors for lymphoma

Cerhan¹,

Slager

2015

Blood

143

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Our understanding of familial predisposition to lymphoma (collectively defined as non-Hodgkin lymphoma [NHL], Hodgkin lymphoma [HL], and chronic lymphocytic leukemia [CLL]) outside of rare hereditary syndromes has progressed rapidly during the last decade. First-degree relatives of NHL, HL, and CLL patients have an ∼1.7-fold, 3.1-fold, and 8.5-fold elevated risk of developing NHL, HL, and CLL, respectively. These familial risks are elevated for multiple lymphoma subtypes and do not appear to be confounded by nongenetic risk factors, suggesting at least some shared genetic etiology across the lymphoma subtypes. However, a family history of a specific subtype is most strongly associated with risk for that subtype, supporting subtype-specific genetic factors. Although candidate gene studies have had limited success in identifying susceptibility loci, genome-wide association studies (GWAS) have successfully identified 67 single nucleotide polymorphisms from 41 loci, predominately associated with specific subtypes. In general, these GWAS-discovered loci are common (minor allele frequency >5%), have small effect sizes (odds ratios, 0.60-2.0), and are of largely unknown function. The relatively low incidence of lymphoma, modest familial risk, and the lack of a screening test and associated intervention, all argue against active clinical surveillance for lymphoma in affected families at this time.

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Section: Linkage Studiesmentioning

confidence: 99%

Section: Genetic Association Studiesmentioning

confidence: 99%

Section: Genetic Association Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Familial predisposition and genetic risk factors for lymphoma

Cerhan¹,

Slager

2015

Blood

143

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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.…”

mentioning

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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Hodgkin Lymphoma

Portlock

Kumar

Armitage³

2017

Holland‐Frei Cancer Medicine

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Overview This chapter provides a historical perspective on the marked advances in radiotherapy and chemotherapy that have contributed to significant improvements in the curability of Hodgkin lymphoma (HL) over the past several decades. The classic features and new insights into the epidemiology, biology, and pathologic characteristics of HL are described. With emphasis on the modern clinical approach to the staging, imaging, and treatment of HL, the chapter highlights how current management approaches, such as refined risk stratification, use of PET imaging, and the reduction of radiation field and dose, seek to limit long‐term toxicities of therapy while maintaining excellent cure rates. Finally, the authors describe how the development of novel, biologically targeted therapies has contributed to significant changes in the therapeutic landscape for patients with relapsed, refractory HL.

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Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms

Cited by 49 publications

References 72 publications

Familial predisposition and genetic risk factors for lymphoma

Familial predisposition and genetic risk factors for lymphoma

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

Hodgkin Lymphoma

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