Inherited predisposition to multiple myeloma

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. In addition, several targets of paraproteins (so called 'paratargs') in MM have been identified. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions.

Direct evidence for a polygenic etiology in familial multiple myeloma

“…4,5 Since the 1920s, several authors have reported families with multiple cases of MM, including families both with Mendelian and non-Mendelian pedigrees. 6,7 In the 2000s, systematic family studies, including in population-based registries, confirmed that first-degree relatives of patients with MM and its precursor condition, monoclonal gammopathy of unknown significance, have 2 to 4 times higher risk for MM, [8][9][10][11][12][13] and a higher risk for lymphomas and certain solid tumors. 14,15 According to estimates based on Swedish nationwide registries, about 2.4% of MM cases have a first-degree relative with MM.…”

Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium

“…Hyperphosphorylation of other autoantigenic paraprotein targets, including paratargs 2,5,6,8,9,10 and 11, have been identified in MM patients (Koura & Langston, ). Human leucocyte antigen (HLA) types, including HLA‐Cw2 and HLA‐B18, have been investigated as potentially associated with MM (Koura & Langston, ). Additionally, genome wide association studies (GWAS) have identified regions on chromosomes 3p22, 7p15·3 and 2p23·3 as potentially associated with MM (Broderick et al , ; Koura & Langston, ).…”

“…Human leucocyte antigen (HLA) types, including HLA‐Cw2 and HLA‐B18, have been investigated as potentially associated with MM (Koura & Langston, ). Additionally, genome wide association studies (GWAS) have identified regions on chromosomes 3p22, 7p15·3 and 2p23·3 as potentially associated with MM (Broderick et al , ; Koura & Langston, ). The SNP rs2456449 polymorphism on chromosome 8q24, associated with CLL (Crowther‐Swanepoel et al , ), has also been associated with MM (Campa et al , ).…”

“…In a large, Swedish population‐based case‐control study, first‐degree relatives of MM patients had over twice the risk of developing MM, compared to first‐degree relatives of controls (Kristinsson et al , ). Familial aggregation of MM and of MM with the premalignant state, monoclonal gammopathy of undetermined significance (MGUS), has also been documented (Shoenfeld et al , ; Bizzaro & Pasini, ; Ogmundsdottir et al , ; Coleman et al , ; Steingrimsdottir et al , ; Greenberg et al , ; Koura & Langston, ). In a large, population‐based study in Sweden, first‐degree relatives of MGUS patients had a nearly 3 times the risk of developing MM compared to first‐degree relatives of controls (Risk ratio: 2·9, 95% CI: 1·9–4·3) (Landgren et al , ).…”

Multiple Myeloma: New Perspectives

“…Most studies suggest that MM has a possible hereditary influence [5]. The risk of MM goes up as people age.…”