Familial predisposition and genetic risk factors for lymphoma

Abstract

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.

Figure 1

GWAS-discovered loci for lymphoma subtypes mapped to chromosomal location. Except for 6p21 and 8q24, there is minimal or little overlap of loci for lymphoma subtype-specific susceptibility loci. Lym, lymphoma.

Figure 2

Lymphoma susceptibility loci by effect size and AF. The blue diamonds represent established lymphoma susceptibility loci plotted by AF (x-axis) vs effect size (y-axis). For lymphoma, most of the loci are common variants of low to modest effect size (mainly discovered by GWAS), although a few low-frequency variants have been identified. No rare alleles of low frequency (generally identified through linkage studies and sequencing) have been definitively linked to lymphoma. Very rare variants of low effect size are difficult to identify using current genetic approaches, whereas there are very few examples of common variants of high effect size for common diseases (and none in lymphoma).