Inherited susceptibility to MM: evidence for a polygenic etiology

The question of inherited susceptibility to Multiple Myeloma (MM) and genetic background of familial MM has long gone unanswered. In April 2017, Britt-Marie Halvarsson and Bjorn Nilsson from The Department of Laboratory Medicine, Lund University, Lund, Sweden, and collaborators, published a paper in Blood Advances, in which they demonstrated an enrichment of common MM risk alleles in familial MM compared with sporadic MM.

Study Design

• Patients (pts) with familial MM were identified using the Swedish Cancer Registry and the Swedish Multi-generation Registry; 237 pts diagnosed between 1958 and 2013 who had at least one first- or second-degree relative with MM were identified
• Samples from 36 of these patients (24 families) were obtained (from the Swedish National Myeloma Biobank), along with 2 second-degree relatives from Norway
• Clinical characteristics between familial and sporadic cases were comparable
• Samples were analyzed using Illumina OmniExpress SNP microarrays; genotypes of tag SNPs for 16 risk loci associated with MM were quantified
• Risk allele burden was calculated using 2 different scores - total number of risk alleles and number of risk alleles weighted by their log-transformed odds ratios (ORs) across all loci
• Gene scores from same family members were averaged
• Corresponding values were calculated using scores from pre-existing sets of SNP microarray data (1,530 sporadic MM cases in Sweden and 10,171 population-based controls)

Key Highlights

• An enrichment of risk alleles was observed in familial cases compared with sporadic cases: average number of risk alleles = 14.9 vs 14.1 (1-sided Student t test, P = 4.8 x 10^-2); sum of log OR = 2.55 vs 2.42 (P = 6.0 x 10^-2)
• Population-based controls: average number of risk alleles = 14.9 vs 13.2 (P = 1.5 x 10^-4); sum of log OR = 2.55 vs 2.25 (P = 1.3 x 10^-4)
• Most individual risk alleles occurred at higher frequencies in familial cases vs sporadic cases, although only one of the individual alleles reached statistical significance after correction for multiple testing
• Most common risk alleles:
  • CCAT1 (risk allele frequency = 0.55 vs 0.38; uncorrected Cochran-Armitage trend test P = 0.002; Bonferroni-corrected P = 0.033)
  • ELL2 (risk allele frequency = 0.89 vs 0.77; uncorrected P = 0.011; corrected P = 0.16)
• No difference in age of onset: familial vs sporadic cases = 66.0 vs 68.4 years (t test P = 0.22)
• No difference in polygenic risk scores between men and women across all study groups (t test P = 0.21-0.75)
• The proportion of familial MM cases that associate with enrichment of common risk alleles was assessed
• Such a risk score can be calculated from one of two distributions: a right-shifted distribution -  usually observed for cases caused by enrichment of common risk alleles, or a similar distribution to population controls
• In order to estimate the proportions of these two underlying distributions, a two-component Gaussian mixture model was fitted to the observed risk scores of familial MM
• For the number-of-risk-alleles score, the proportion of the component representing cases caused by a high risk allele burden was estimated to be 32% (90% CI, 19%-53%); mean = 17.6 compared with 13.2 for controls
• Sum-of-log-OR score, the corresponding proportion was estimated at 37% (90% confidence interval, 21%-65%); mean = 2.91 compared with 2.25 for controls
• This indicates that approximately one third of familial cases are caused by enrichments of common MM risk alleles
• To see whether familial MM was due to rare mutations not represented in SNP microarray data, 29 of the Swedish cases and 6 cases from Germany were analyzed by whole-exome sequencing, but no variants were detected

In conclusion, a direct association between polygenic etiology in MM was identified, but future sequencing efforts of larger populations are required for further clarity. Limitations of the study were the small sample size, which did not allow exome-wide screening for rare mutations, and the fact that cases of monoclonal gammopathy of unknown significance (MGUS) were not recorded in the registry.

Abstract

Although common risk alleles for multiple myeloma (MM) were recently identified, their contribution to familial MM is unknown. Analyzing 38 familial cases identified primarily by linking Swedish nationwide registries, we demonstrate an enrichment of common MM risk alleles in familial compared with 1530 sporadic cases (P = 4.8 × 10⁻² and 6.0 × 10⁻², respectively, for 2 different polygenic risk scores) and 10 171 population-based controls (P = 1.5 × 10⁻⁴ and 1.3 × 10⁻⁴, respectively). Using mixture modeling, we estimate that about one-third of familial cases result from such enrichments. Our results provide the first direct evidence for a polygenic etiology in a familial hematologic malignancy.