Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

Physicians' strategies for using family history data: having the data is not the same as using the data.

OBJECTIVE: To identify needs in a clinical decision support tool development by exploring how primary care providers currently collect and use family health history (FHH). DESIGN: Survey questionnaires and semi-structured interviews were administered to a mix of primary and specialty care clinicians within the University of Utah Health system (40 surveys, 12 interviews). RESULTS: Three key themes emerged regarding providers' collection and use of FHH: (1) Strategies for collecting FHH vary by level of effort; (2) Documentation practices extend beyond the electronic health record's dedicated FHH module; and (3) Providers desire feedback from genetic services consultation and are uncertain how to refer patients to genetic services. CONCLUSION: Study findings highlight the varying degrees of engagement that providers have with collecting FHH. Improving the integration of FHH into workflow, and providing decision support, as well as links and tools to help providers better utilize genetic counseling may improve patient care.

Critical care information display approaches and design frameworks: A systematic review and meta-analysis.

OBJECTIVE: To systematically review original user evaluations of patient information displays relevant to critical care and understand the impact of design frameworks and information presentation approaches on decision-making, efficiency, workload, and preferences of clinicians. METHODS: We included studies that evaluated information displays designed to support real-time care decisions in critical care or anesthesiology using simulated tasks. We searched PubMed and IEEExplore from 1/1/1990 to 6/30/2018. The search strategy was developed iteratively with calibration against known references. Inclusion screening was completed independently by two authors. Extraction of display features, design processes, and evaluation method was completed by one and verified by a second author. RESULTS: Fifty-six manuscripts evaluating 32 critical care and 22 anesthesia displays were included. Primary outcome metrics included clinician accuracy and efficiency in recognizing, diagnosing, and treating problems. Implementing user-centered design (UCD) processes, especially iterative evaluation and redesign, resulted in positive impact in outcomes such as accuracy and efficiency. Innovative display approaches that led to improved human-system performance in critical care included: (1) improving the integration and organization of information, (2) improving the representation of trend information, and (3) implementing graphical approaches to make relationships between data visible. CONCLUSION: Our review affirms the value of key principles of UCD. Improved information presentation can facilitate faster information interpretation and more accurate diagnoses and treatment. Improvements to information organization and support for rapid interpretation of time-based relationships between related quantitative data is warranted. Designers and developers are encouraged to involve users in formal iterative design and evaluation activities in the design of electronic health records (EHRs), clinical informatics applications, and clinical devices.

Novel displays of patient information in critical care settings: a systematic review.

OBJECTIVE: Clinician information overload is prevalent in critical care settings. Improved visualization of patient information may help clinicians cope with information overload, increase efficiency, and improve quality. We compared the effect of information display interventions with usual care on patient care outcomes. MATERIALS AND METHODS: We conducted a systematic review including experimental and quasi-experimental studies of information display interventions conducted in critical care and anesthesiology settings. Citations from January 1990 to June 2018 were searched in PubMed and IEEE Xplore. Reviewers worked independently to screen articles, evaluate quality, and abstract primary outcomes and display features. RESULTS: Of 6742 studies identified, 22 studies evaluating 17 information displays met the study inclusion criteria. Information display categories included comprehensive integrated displays (3 displays), multipatient dashboards (7 displays), physiologic and laboratory monitoring (5 displays), and expert systems (2 displays). Significant improvement on primary outcomes over usual care was reported in 12 studies for 9 unique displays. Improvement was found mostly with comprehensive integrated displays (4 of 6 studies) and multipatient dashboards (5 of 7 studies). Only 1 of 5 randomized controlled trials had a positive effect in the primary outcome. CONCLUSION: We found weak evidence suggesting comprehensive integrated displays improve provider efficiency and process outcomes, and multipatient dashboards improve compliance with care protocols and patient outcomes. Randomized controlled trials of physiologic and laboratory monitoring displays did not show improvement in primary outcomes, despite positive results in simulated settings. Important research translation gaps from laboratory to actual critical care settings exist.

Critical care information display approaches and design frameworks: A systematic review and meta-analysis.

OBJECTIVE: To systematically review original user evaluations of patient information displays relevant to critical care and understand the impact of design frameworks and information presentation approaches on decision-making, efficiency, workload, and preferences of clinicians. METHODS: We included studies that evaluated information displays designed to support real-time care decisions in critical care or anesthesiology using simulated tasks. We searched PubMed and IEEExplore from 1/1/1990 to 6/30/2018. The search strategy was developed iteratively with calibration against known references. Inclusion screening was completed independently by two authors. Extraction of display features, design processes, and evaluation method was completed by one and verified by a second author. RESULTS: Fifty-six manuscripts evaluating 32 critical care and 22 anesthesia displays were included. Primary outcome metrics included clinician accuracy and efficiency in recognizing, diagnosing, and treating problems. Implementing user-centered design (UCD) processes, especially iterative evaluation and redesign, resulted in positive impact in outcomes such as accuracy and efficiency. Innovative display approaches that led to improved human-system performance in critical care included: (1) improving the integration and organization of information, (2) improving the representation of trend information, and (3) implementing graphical approaches to make relationships between data visible. CONCLUSION: Our review affirms the value of key principles of UCD. Improved information presentation can facilitate faster information interpretation and more accurate diagnoses and treatment. Improvements to information organization and support for rapid interpretation of time-based relationships between related quantitative data is warranted. Designers and developers are encouraged to involve users in formal iterative design and evaluation activities in the design of electronic health records (EHRs), clinical informatics applications, and clinical devices.

Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747-59. ©2018 AACR.

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR.