KDM1A is first identified germline MM predisposition gene

Almost all cases of multiple myeloma (MM) are preceded by monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant condition which is typically asymptomatic. Therefore, a focus on identifying predisposition genes is highly relevant in MM. Unraveling MM genetics in order to identify key mutations could help predict an individual’s risk of developing MM (including relatives of MM patients), as well as help improve diagnosis and treatment.

Xiaomu Wei, and M. Nieves Calvo-Vidal from Biological Statistics and Computational Biology, Cornell University, New York, US, and colleagues, conducted a study to identify novel germline predisposition genes for MM and published their findings in Cancer Research in March 2018.

Key Findings:

• Whole-exome sequencing, N = 50 samples from patients (pts) with familial MM
• Germline N-terminal truncating mutations were identified in familial MM in lysine-specific demethylase 1 (LSD1/KDM1A – an epigenetic transcriptional repressor)
  • Pedigree of early-onset MM carrying germline KDM1A c.805_806delAG (p.Arg269Aspfs*7)
  • Pedigree early onset myeloma proband carrying KDM1A c.707delA (p.Gln236Hisfs*3) mutation – family member affected by other cancers
  • Somatic loss of heterozygosity (LOH) in germline and MM samples was observed in 2/3 of the MM pts carrying KDM1A c.805_806delAG (p.Arg269Aspfs*7)
  • Western blot revealed KDM1A null (-/-) lymphoblastoid cell lines (LCL) and increased mono-methylation of H3K4 (H3K4me1)
• Germline truncating KDM1A mutations were found in early-onset MM pts
• Enrichment of KDM1A loss-of-function (LOF) mutations among familial and early-onset MM pts vs controls: Relative Risk (RR) = 23.28, (95% CI, 4.85­-111.75), P = 0.005)
• Significant enrichment of deleterious KDM1A mutations in sporadic MM patients vs controls: Deleterious: 9 (1.23%) vs 2 (0.14%); Benign: 724 (98.77%) vs 1478 (99.86%); P = 0.00127
• Analysis of transcriptome databases revealed significantly lower mRNA levels in MGUS and MM cells vs plasma cells (PCs): 7.45x10^-6 vs 1.7x10^-05, moderated t-test
• This suggests a broader role for KDM1A inactivation in sporadic MGUS and MM
• Higher vulnerability to epigenetic dysregulation from KDM1A haplo-insufficiency/LOF mutations for MGUS and MM cells
• A KDM1A inhibitor (GSK-LSD1) was injected into C57BL/6 mice and showed:
  • Increased splenic plasma cells (PCs)
  • IgM to IgG2b isotype class switching
  • Stimulation of a secondary immune response to NP-CGG
  • Increase in Ig production
  • Upregulation of Myc-driven MM oncogenes CCND1 and CCND2
• Carriers of KDM1A mutations had increased CCND2 and alterations in other pathways in their MM cells compared to matched controls

The authors conclude that KDM1A is the first gene identified as an autosomal dominant MM predisposition gene, with truncating and predicted deleterious missense mutations occurring at a higher frequency in MM patients. There was also an enrichment of pathways associated with intrinsic MM pathogenesis and MYC target genes, in the tumor transcriptome of patients with mutant KDM1A.