Dataset Information

Germline variants at SOHLH2 influence multiple myeloma risk.

ABSTRACT: Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10^-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

SUBMITTER: Duran-Lozano L

PROVIDER: S-EPMC8055668 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Germline variants at SOHLH2 influence multiple myeloma risk.

Duran-Lozano Laura L Thorleifsson Gudmar G Lopez de Lapuente Portilla Aitzkoa A Niroula Abhishek A Went Molly M Thodberg Malte M Pertesi Maroulio M Ajore Ram R Cafaro Caterina C Olason Pall I PI Stefansdottir Lilja L Bragi Walters G G Halldorsson Gisli H GH Turesson Ingemar I Kaiser Martin F MF Weinhold Niels N Abildgaard Niels N Andersen Niels Frost NF Mellqvist Ulf-Henrik UH Waage Anders A Juul-Vangsted Annette A Thorsteinsdottir Unnur U Hansson Markus M Houlston Richard R Rafnar Thorunn T Stefansson Kari K Nilsson Björn B

Blood cancer journal 20210419 4

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10<sup>-14</sup>). This gene encodes a transcription factor i ...[more]

PMID: 33875642

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Project description:Genomic instability, a well-established hallmark of human cancer, is also a driving force in the natural history of multiple myeloma (MM) - a difficult to treat and in most cases fatal neoplasm of immunoglobulin producing plasma cells that reside in the hematopoietic bone marrow. Long recognized manifestations of genomic instability in myeloma at the cytogenetic level include abnormal chromosome numbers (aneuploidy) caused by trisomy of odd-numbered chromosomes; recurrent oncogene-activating chromosomal translocations that involve immunoglobulin loci; and large-scale amplifications, inversions, and insertions/deletions (indels) of genetic material. Catastrophic genetic rearrangements that either shatter and illegitimately reassemble a single chromosome (chromotripsis) or lead to disordered segmental rearrangements of multiple chromosomes (chromoplexy) also occur. Genomic instability at the nucleotide level results in base substitution mutations and small indels that affect both the coding and non-coding genome. Sometimes this generates a distinctive signature of somatic mutations that can be attributed to defects in DNA repair pathways, the DNA damage response (DDR) or aberrant activity of mutator genes including members of the APOBEC family. In addition to myeloma development and progression, genomic instability promotes acquisition of drug resistance in patients with myeloma. Here we review recent findings on the genetic predisposition to myeloma, including newly identified candidate genes suggesting linkage of germline risk and compromised genomic stability control. The role of ethnic and familial risk factors for myeloma is highlighted. We address current research gaps that concern the lack of studies on the mechanism by which germline risk alleles promote genomic instability in myeloma, including the open question whether genetic modifiers of myeloma development act in tumor cells, the tumor microenvironment (TME), or in both. We conclude with a brief proposition for future research directions, which concentrate on the biological function of myeloma risk and genetic instability alleles, the potential links between the germline genome and somatic changes in myeloma, and the need to elucidate genetic modifiers in the TME.

Dataset Information

Germline variants at SOHLH2 influence multiple myeloma risk.

Publications

Germline variants at SOHLH2 influence multiple myeloma risk.

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