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.

Non-Hodgkin lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Primary immunodeficiencies (PID) such as DNA repair defects (Nijmegen breakage syndrome, Ataxia telangiectasia, Bloom syndrome or constitutional mismatch repair deficiency), severe combined immunodeficiencies (SCID), common variable immunodeficiencies (CVID), and immune-osseous dysplasias (Di George syndrome or cartilage hair hypoplasia) have an extraordinary risk of developing leukemia and lymphoma. [5][6][7][8][9][10][11][12][13][14][15][16][17]20,21 Although these patients seem to have an inferior prognosis and an increased risk of treatment-related toxicity and death compared to patients with lymphoid malignancies without a PID, curative therapies including allogeneic stem cell transplantation (allo-SCT) have been repeatedly reported. 5,6,10,11,15,16,22 Systematic data on the spectrum of common and rare pre-existing conditions associated with NHL in children and adolescents are scarce with respect to the type of the pre-existing conditions and the clinical characteristics and outcome of the associated NHL subtypes.…”

Chronic lymphocytic leukemia (CLL)—Then and now

“…Five year relative survival was 67.5% in 1975 to 87.9% in 2007 [6,7]. Incidence of CLL is higher in individuals with family history of CLL [8] patients with Caucasian ethnicity and agent orange exposure. Clinically, the patients commonly present with asymptomatic peripheral blood lymphocytosis or leukocytosis (predominantly lymphocytosis), lymphadenopathy, hepatosplenomegaly, bone marrow failure, and recurrent infections and often with autoimmune hemolytic anemia or autoimmune thrombocytopenia.…”

Shelterins, a genetic crossroad in CLL

“…Moreover, it was believed that aged neutrophils might migrate poorly to sites of inflammation as their expression of CXCR2, the receptor for several major neutrophil-targeted chemokines, such as CXCL8/interleukin-8, is decreased. 2 The discovery that these "age-wise" cells are the first and dominant subtype of neutrophil to be recruited to the sites of infection sheds new light on efficiency and adaptability of the immune system.…”

“…In the absence of infection, where neutrophils are recruited to and die within inflammatory sites, neutrophils in circulation do not die in the bloodstream but rather are eliminated in bone marrow (predominant site), spleen, or liver by specialized macrophages. 2 Recently, it has been shown that the aging of neutrophils is microbiota-driven and depends on Toll-like receptors (TLRs), including TLR-2 and TLR-4,…”