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.

Introduction

Multiple myeloma (MM) is a plasma cell neoplasm that accounts for 0.8% of cancer cases worldwide and comprises about 13% of hematologic malignancies [Ferlay et al. 2010; Kyle and Rajkumar, 2004]. The disease is characterized by infiltration of the bone marrow, bones and sometimes other tissues by malignant plasma cells, which typically produce a monoclonal paraprotein. Common clinical manifestations include lytic bony lesions, renal impairment, anemia, hypercalcemia and immune dysfunction. MM may be preceded by a monoclonal gammopathy of undetermined significance (MGUS), which is present in about 3% of the general population over the age of 50 years, and carries a risk of progression to MM of about 1% per year [Kyle et al. 2006].

Surveillance Epidemiology and End Results (SEER) data indicate that, in the United States, the median age at diagnosis of MM is 69 years, with an age-adjusted incidence of 5.8 cases per 100,000 persons per year. About 75% of MM cases are diagnosed in persons over 50 years of age. It is estimated that in 2012, 21,700 people will be diagnosed and 10,710 people will die of MM in the US.

The incidence of MM varies widely, ranging from 0.4 to 5 cases per 100,000 persons, with the highest rates in Australia, New Zealand, North America and parts of Europe, and the lowest rates in Asia [Parkin et al. 2005]. Striking racial differences in MM have long been noted, with the incidence in the black population being approximately twice that of the white population in the US. Alternatively, the risk of MM is very low in individuals of Asian descent [Howlader et al. 2012].

While the causes of MM remain poorly understood, factors affecting risk for development of the disease include age, gender, racial and ethnic background, underlying immunodeficiency, exposure to radiation, exposure to dioxin-related compounds, and family history of MM and other hematolymphoid neoplasms [Alexander et al. 2007]. Several lines of direct and indirect evidence also suggest the existence of inherited factors, which may predispose individuals to development of MM, MGUS and other related cancers. Here we focus on available data in this area and highlight future research directions.

Myeloma in families

The idea of a potential familial predisposition to MM was first advanced in the 1920s. In 1925, Meyerding highlighted 13 cases of MM; in his series, one patient with myeloma had an aunt with a bone disease with a fractured leg [Meyerding, 1925]. In a review of MM published in 1928, Geshickter and Copeland briefly mention a case in which two siblings both died of myeloma [Geschickter and Copeland, 1928]. In 1954, the first detailed case report of two sisters with proven MM was published by Mandema and Wildervanck [Mandema and Wildervanck, 1954]. By 1965, there were at least 10 published reports of families with 2 or more affected members [Alexander and Benninghoff, 1965] and families with many combinations of affected members were described. More recently, one report described 39 families with multiple members affected by MM and related disorders (MGUS, Waldenström macroglobulinemia [WM], amyloidosis or cryoglobulinemia) [Lynch et al. 2005], and another detailed 8 African American families with multiple cases of MM or MGUS [Jain et al. 2009]. The patterns of cases in these families do not follow a simple Mendelian pattern, suggesting a more complex genetic basis for the phenotype. A curious aspect of the latter two reports is the observation of anticipation, which is the occurrence of disease at an earlier age in later generations. This type of inheritance has been most closely associated with disorders involving trinucleotide repeat errors such as Fragile X syndrome and muscular dystrophies [Monckton and Caskey, 1995]. Nevertheless, it is important to remember that with cancer phenotypes there may be an element of ascertainment bias related to heightened awareness of the disease, so the observation of anticipation should be interpreted with caution. To date, over 100 families with multiple affected members with myeloma or other plasma cell dyscrasias have been described and these provide strong evidence for the existence of inherited risk factors for MM.

There are a few hints that the risk of MM may also be modestly increased in association with several more well-defined cancer family syndromes. An excess of MM has been noted among first-degree relatives of Ashkenazi Jewish carriers of common BRCA1 and BRCA2 mutations [Struewing et al. 1997]. Sobol and colleagues later described a family with multiple cases of MM in which two of the affected members also developed breast cancer. Genotyping of one of these doubly affected women revealed a nonsense mutation in the BRCA2 gene [Sobol et al. 2002]. Finally, Dilworth and colleagues described a melanoma-prone family in which a germline mutation in CDKN2A (p16) was found in a family member with MM; they went on to demonstrate loss of the normal allele in the malignant plasma cells, suggesting a pathogenic role in tumor development [Dilworth et al. 2000]. While these observations are circumstantial, they support the notion that susceptibility to MM can occur though general mechanisms common to a number of seemingly unrelated tumor types.

Case-control and cohort studies

Case-control studies also support the existence of inherited risk factors for the development of MM and point to an association with other hematolymphoid malignancies. Bourguet and colleagues performed a hospital-based case-control study to assess whether people with a family history of cancers including MM were at increased risk of developing MM [Bourguet et al. 1985]. They looked at 439 cases of MM seen at Duke University Medical Center between 1967 and 1982 as well as 1317 matched controls. Of these groups, three cases and four controls had a family member with MM. In this analysis, individuals with a family history of cancer of any type had a relative risk for MM of 1.4 (95% confidence interval [CI] 0.5–10.1), and those with a family history of MM had a relative risk of 2.4 (95% CI 1.1–1.8). Another population-based case-control study in Sweden examined 229 cases with myeloma and 220 controls [Eriksson and Hallberg, 1992]. They found an increased risk for myeloma among persons with first-degree relatives with hematologic malignancies (relative risk [RR] 2.36, 90% CI 0.9–6.15) and MM (RR 5.64, 90% CI 1.16–27.51). In addition, other malignancies were examined, and persons with first-degree relatives with prostate cancer and brain tumors had an increased risk for MM, with RR 3.11 (90% CI 1.25–7.71) and 6.61 (90% CI 1.42–30.67), respectively.

Given the higher incidence of MM in blacks than whites, Brown and colleagues separated black and white patients with myeloma in a population-based case-control study that included 361 white persons and 204 black persons with myeloma [Brown et al. 1999]. They observed an increased risk of MM among individuals with a family history of any hematolymphoid cancer, with an odds ratio (OR) of 1.7 (95% CI 1.0–2.8). The highest risk of MM was seen in persons with a family history of MM in a first-degree relative, which was associated with an OR of 3.7 (95% CI 1.2–12). In their study, the OR for myeloma was 17.4 (95% CI 2.4–348) among black individuals with a first-degree relative with MM and 1.5 (95% CI 0.3–6.4) for white individuals with similar family history. Significant associations with other nonhematologic cancer types were not observed in this study.

The largest case-control study focused on myeloma included 13,896 Swedish MM patients and 54,365 matched controls, and assessed rates of hematologic malignancies, MGUS and solid tumors in first-degree relatives [Kristinsson et al. 2009]. First-degree relatives of people with MM had a higher risk of developing MM (RR 2.1, 95% CI 1.6–2.9), MGUS (RR 2.1; CI 1.5–3.1), ALL (RR 2.1, CI 1.0–4.2) and any solid tumor (RR 1.1, CI 1.0–1.1).

HLA associations with myeloma

A number of studies have evaluated the possible association of MM with certain human leukocyte antigen (HLA) types. Mason and Cullen evaluated 63 myeloma patients in comparison with 83 healthy controls, and noted an increased frequency of HLA-A5 in patients with myeloma [Mason and Cullen, 1975]. In 1983, Leech and colleagues looked specifically at black myeloma patients in Louisiana, and used a control group of 138 normal healthy black males from the same area. They saw no significant relationship between HLA-A or HLA-B serotypes and myeloma; however, HLA-Cw5 was seen in a higher proportion of myeloma patients than healthy controls (RR 15) [Leech et al. 1982]. Interpretation of these early observations is limited by the crude state of characterization of the HLA loci at the time of the studies, as well as small sample sizes of patient and control groups. Subsequent studies have continued to show varying results, including possible associations with HLA-Cw2 [Pottern et al. 1992] and HLA-B18 [Patel et al. 2002]. Taken together, it is difficult at this point to draw firm conclusions regarding associations with particular HLA antigens or haplotypes, but this is an area of active investigation in the era of sequence-based HLA typing techniques.

Hyperphosphorylated ‘paratargs’ and myeloma risk

In 2009, Preuss and Grass used a modified SEREX (Serological Identification of Recombinantly Expressed Clones) approach to screen a human fetal brain derived protein macroarray with the sera of 192 patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) MM or MGUS, and found that 29 of 192 paraproteins (15.1%) reacted with a single target protein which they called paraprotein target 7, or paratarg-7 [Preuss et al. 2009]. Sequence analysis demonstrated that paratarg-7 is a ubiquitously expressed protein also known as STOML2, and its natural function remains unclear. The same group went on to demonstrate that, while the DNA sequence of paratarg-7 in patients and healthy controls is identical, patients with a paratarg-7-directed paraprotein carry a hyperphosphorylated form of the paratarg-7 protein (pP-7) [Grass et al. 2009]. This analysis has now been extended to include patients with WM and immunoglobulin M (IgM) MGUS, and 11% of these patients demonstrated paraproteins directed toward pP-7 [Grass et al. 2011d]. It is not yet clear whether the clinical features of patients with pP-7 specific paraproteins are different from those of other patients. Taken together, these studies suggest that pP-7 may represent a unique antigenic target, with a propensity to generate immune responses that eventually lead to malignant transformation of plasma cells.

Examination of family members of MM/MGUS patients with anti-paratarg-7 paraproteins has demonstrated that pP-7 is inherited in an autosomal dominant manner [Grass et al. 2009]. In a recent study of four families with familial MM/MGUS, paraproteins from affected members of two of the families were found to target pP-7. Paraproteins from four affected members of a third family targeted a different phosphorylated protein, termed pP-8, which is encoded by the ATG13 gene and is also inherited in its hyperphosphorylated form in an autosomal dominant fashion [Grass et al. 2011b]. Other autoantigenic paraprotein targets (paratargs 2, 5, 6, 7, 8, 9, 10 and 11) have also been identified in small numbers of patients and in each case the proteins are hyperphosphorylated in affected patients. These data support the hypothesis that hyperphosphorylation of selected proteins may be a common mechanism leading to development of autoreactive plasma cell clones [Grass et al. 2011c]. Recent data from the same group suggest that the hyperphosphorylated state of these antigenic targets is a result of alterations in genes/proteins in the phosphorylation/dephosphorylation machinery upstream of phosphatase 2A [Preuss et al. 2011] and linkage analysis implicates a locus on chromosome 4q35 [Grass et al. 2011c].

Initial studies on paratarg-7, which were performed in German MM and MGUS patients, demonstrated the presence of pP-7 (and a pP-7-directed paraprotein) in 13.9% of a series of 252 consecutive patients and 2% of population controls; the relative risk for pP-7 carriers developing MM/MGUS was 7.9 [Grass et al. 2009]. In a study of Japanese patients and controls, the prevalence of pP-7 was 4.5% among patients and 0.36% among controls, and the relative risk of pP-7 carriers developing MM/MGUS was 13.1 [Grass et al. 2011a]. The highest prevalence of pP-7 has been observed among African American MM/MGUS patients, where 28% of patients were noted to carry the hyperphosphorylated form of the protein [Grass et al. 2011c]. While much more population-based work is needed, it appears that differential frequencies of pP-7 (and possibly other hyperphosphorylated proteins) in distinct populations may account for some of the observed difference in the incidence of MM and associated disorders across different ethnic and geographic groups.

Genome-wide association studies

In the 1980s and 1990s, a number of cancer susceptibility genes were identified through linkage analysis in high-risk families. Mutations in these genes, which are associated with breast and ovarian cancer (BRCA1 and BRCA2) [Hall et al. 1990; Wooster et al. 1994], colorectal cancer (APC and mismatch repair genes MLH1 and MSH2) [Bodmer et al. 1987; Lindblom et al. 1993; Peltomaki et al. 1993] and melanoma (CKDN2A) [Cannon-Albright et al. 1992] produce highly penetrant phenotypes, but mutations are rare and account for the minority of ‘familial’ cancers. Statistical and epidemiological studies suggest that most of the inherited susceptibility to common cancers is likely to result from inheritance of multiple genetic variants, each of which has a small to moderate effect. This model of inheritance requires study of much larger numbers of cases and necessitates use of alternative methods of genetic analysis.

Over the past decade, genome-wide association studies (GWASs) have emerged as a powerful tool for large-scale genetic studies, as this approach allows the entire genome to be efficiently interrogated through analysis of single nucleotide polymorphisms (SNPs) in large populations of affected and unaffected individuals. Furthermore, the method complements earlier approaches that target specific candidate genes. To date, GWASs have localized over 150 candidate regions harboring potential susceptibility loci for a variety of different cancer types [Amos et al. 2008; Amundadottir et al. 2006, 2009; Crowther-Swanepoel et al. 2010; Di Bernardo et al. 2008; Eeles et al. 2008; Gudmundsson et al. 2008; Kiemeney et al. 2009; McKay et al. 2008; Papaemmanuil et al. 2009; Shete et al. 2009; Trevino et al. 2009; Wang et al. 2008; Wrensch et al. 2009; Wu et al. 2009]. Notably, at least seven distinct regions have been associated with multiple different tumor types, suggesting related or common mechanisms underlying predisposition.

The one published GWAS in MM has produced interesting preliminary results. Broderick and colleagues conducted a GWAS using MM cases and controls from separate cohorts in the UK and Germany [Broderick et al. 2012]. Their analysis identified two genomic regions that were significantly associated with MM at 3p22 and 7p15.3, as well as a third region at 2p23.3, which had a weaker association. Subsequently, Martina and colleagues genotyped SNPs of interest within these three regions in an additional 1139 MM cases and 1352 controls, and validated the associations in their own study population [Martino et al. 2012]. Current studies are aimed at more detailed analysis of the regions of interest in order to identify the causative polymorphisms. Interestingly, the 7p15.3 region contains a gene, CDCA7L, which is a MYC interacting gene [Huang et al. 2005; Maertens et al. 2006], making it a logical candidate gene for further analysis.

Another study examined genetic variation in the 8q24 region in MM, based on previous GWASs that have demonstrated associations of this general region with risk of glioma, chronic lymphocytic leukemia (CLL), and breast, prostate, bladder, colorectal and ovarian cancer [Chung and Chanock, 2011]. In this study, Campa and colleagues genotyped 20 SNPs within the 8q24 region in 1188 MM cases and 2465 controls, and confirmed an association of a SNP within this region with MM [Campa et al. 2012]. Interestingly, this particular SNP has also been specifically associated with CLL, suggesting the possibility of a common susceptibility locus in related B-lineage malignancies [Crowther-Swanepoel et al. 2010].

GWASs have inherent drawbacks, especially in relatively rare diseases such as MM, where the increase in risk is small or modest. Without large numbers of both cases and controls, studies may lack statistical power to identify weaker (less penetrant) associations. Furthermore, large numbers of SNPs must be evaluated to avoid missing important associations. False-negative and false-positive associations may also reflect case and control population selection, particularly in light of the varying rates of disease and allele frequencies in different ethnic groups. In order to overcome these limitations, groups are forming consortia to pool patients and controls for larger scale genetic studies. Examples include the MyelomA Genetics International Consortium (MAGIC) and the International Multiple Myeloma rESEarch (IMMEnSE) consortium [Martino et al. 2012; Morgan et al. 2012].

Conclusion and future directions

Several lines of evidence point to a genetic predisposition to MM and other plasma cell dyscrasias. Until recent years, only case-control studies and reports of occasional high risk families supported this view. More recently, identification of hyperphosphorylated paratarg proteins and identification of putative susceptibility loci by GWASs have provided more firm evidence indicating inherited predisposition to MM and related disorders. The discovery of pP-7 as a frequent target of paraproteins in MM offers a potential link between the old concept of chronic antigenic stimulation as a potential cause of MM, and observations of familial predisposition as well as racial disparities in the incidence of MM. GWASs have to date identified several susceptibility potential regions of interest in MM and further molecular studies aimed at identification of specific genes of interest are ongoing. Although these discoveries are provocative, further work will be required to identify the genes and mechanisms underlying inherited susceptibility to MM, and these studies will be facilitated by the use of additional resources such as family registries and large-scale consortia.