Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma

Abstract

Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T H 17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.

Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

“…These data further highlight the copersistence of upregulation of UCHL1 and CCND2 in t(4;14) high cytogenetic risk MM, which may be involved in disease progression in this MM subgroup. molecular machinery in MM cells, such as the immune system [35], cell cycle regulation [36,37], and cell differentiation and proliferation [38], which can lead to the identification of promising biomarkers and potential therapeutic targets for the treatment of MM.…”

“…Furthermore, t(4;14) was associated with an adverse prognosis in patients who received high-dose chemotherapy with autologous stem cell transplantation (ASCT) [ 32 – 34 ]. Expression profile and functional enrichment analyses yield information about the molecular machinery in MM cells, such as the immune system [ 35 ], cell cycle regulation [ 36 , 37 ], and cell differentiation and proliferation [ 38 ], which can lead to the identification of promising biomarkers and potential therapeutic targets for the treatment of MM.…”

Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease

“…In our series, serotonin was significantly elevated in cases of MM, without, however, having a clear association between higher levels and ISS3. Regarding melatonin and its circadian rhythm controlling activity, recent studies have detected significant associations between disturbances in circadian rhythm and increased risk of developing MM 46 .With the intention of evaluating in more detail the possible effect of this pathway in cases of MM, we compared, from the perspective of the activity of Melatonin Receptor 1 B (Trp/Phe), the controls to MM cases divided according to ISS. The results show significant differences between cases and controls, becoming even more evident in ISS3 cases.…”

Mouse tumor susceptibility genes identify drug combinations for multiple myeloma

“…The one gene in common with our studies is the Cdkn2a locus; it is a tumor susceptibility gene in both mouse plasma cell tumors by genetic linkage studies [ 4 , 6 , 15 ] and in genome-wide association studies (GWAS) in human multiple myeloma [ 52 ] . Much progress has been made in understanding the omics of myeloma through GWAS [ 52 – 57 ] , eQTL [ 58 ] , and WGS [ 35 , 42 ] studies of myeloma patient samples. These studies have helped to identify new targets for intervention of myeloma disease progression and form the basis for developing companion diagnostics for drug treatments.…”