[Show abstract][Hide abstract] ABSTRACT: Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P = 6 x 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P = 0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.
Full-text · Article · Dec 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Type 2-diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between both traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide association studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF-1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (OR=1.32-2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (AUC=0.645 vs. AUC=0.629; P=4.05E-06). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (PInteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs. ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.
Full-text · Article · May 2015 · Endocrine Related Cancer
[Show abstract][Hide abstract] ABSTRACT: Here we perform the first genome wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; p=6 x 10-10). Patients with the minor allele are at increased risk for mortality (HR 2.65; 95% CI: 1.94 - 3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 p=0.044)
Using publically available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival.. Polymorphisms at the FOPNL locus are associated with survival among MM patients.
Full-text · Article · May 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Central nervous system (CNS) involvement in multiple myeloma (MM) is uncommon. Among its possible presentations, leptomeningeal involvement of MM, also termed central nervous system myelomatosis (CNS-MM) is rare and is characterized by the presence of neoplastic plasma cells in the cerebrospinal fluid (CSF). So far, 187 cases of CNS-MM have been reported : the great majority of them were diagnosed by cytological assays and flow cytometry was used in only eight cases. We describe a case of CNS-MM in a 62-year-old woman, previously treated with chemotherapy (VTD) and autologous peripheral blood hematopoietic stem cell transplantation for stage IIIB IgG-λ MM. After achieving a very good partial response, the patient showed progression of disease, with an extramedullary localization. During administration of second-line therapy, the patient showed severe neurological symptoms. MRI resulted negative. Diagnosis of CNS-MM was made by multiparameter flow cytometry, which showed the presence of CD56(+) plasma cells in a CSF sample, in the absence of plasma cell leukemia. In this paper we also present a review of the eight previous cases of CNS-MM diagnosed by flow cytometry. We found that the application of flow cytometry in cases of MM with neurological symptoms allows a rapid diagnosis of CNS-MM and provides useful information about plasma cell phenotype (including CD56 expression). Some cases of CNS-MM are characterized by normal MRI. In addition, some evidences deriving from the review of literature suggest that CSF monitoring by flow cytometry in such cases might be used to evaluate the efficacy of drugs capable of crossing the blood-brain barrier. [J Clin Exp Hematop 54(2) : 129-136, 2014].
No preview · Article · Oct 2014 · Journal of Clinical and Experimental Hematopathology
[Show abstract][Hide abstract] ABSTRACT: Background: Genetic background plays a role in multiple myeloma (MM) susceptibility. Several single nucleotide polymorphisms (SNPs) associated with genetic susceptibility to MM were identified in the last years, but only few of them were validated in independent studies. Methods: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-α), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1498 MM cases and 1934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones. Results: None of the selected SNPs were significantly associated with MM risk (p-value range: 0.055 - 0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. Conclusions: We can exclude that the selected polymorphisms are major MM risk factors. Impact: Independent validations studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in MM risk.
Full-text · Article · Feb 2014 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) associated with fmsrelated tyrosine kinase 3 (FLT3) internal tandem duplication mutation has an increased relapse rate and a reduced overall survival. Here we report 3 cases of advanced refractory AML treated using sorafenib alone or in association with chemotherapy, at a standard dose of 400 mg twice daily. All the patients had been previously treated with several chemotherapy lines and their status was complicated by severe infectious disease. After sorafenib treatment, clinical complete remission but not molecular remission was achieved in all cases. Median duration of the response of these patients was relatively short (40 days), but in 1 patient it was possible to continue the therapy at the reduced dose of 600 mg daily as a bridge to allogeneic stem cell transplantation. We confirm that sorafenib is active in FLT3 mutated AML and we suggest that this drug could be used in more precocious stages of this disease to achieve a deeper hematological response as a bridge to bone marrow transplant.
No preview · Article · Oct 2013 · Clinical lymphoma, myeloma & leukemia
[Show abstract][Hide abstract] ABSTRACT: The exposure to pesticides and toxic compounds in xenobiotic transport and metabolism genes has been shown to affect risk of developing multiple myeloma (MM). Therefore, we hypothesized that genetic variations in xenobiotic transport and metabolism regulator genes PXR (NR1I2) and CAR (NR1I3) could determine a difference in MM susceptibility. Ten tagging single-nucleotide polymorphisms (SNPs) for PXR and seven for the CAR genes were selected and genotyped in 627 MM cases and 883 controls collected in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. None of the 17 SNPs investigated showed significant association with MM risk either alone or when combined in haplotypes. Significant SNP-SNP interactions were not found, neither with 58 previously genotyped polymorphisms in ABC transporters. We can therefore exclude that common genetic variants in the xenobiotic transport and metabolism regulator genes PXR and CAR affect MM risk.Journal of Human Genetics advance online publication, 10 January 2013; doi:10.1038/jhg.2012.149.
Full-text · Article · Jan 2013 · Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: We conducted a retrospective study to compare thalidomide, bortezomib and dexamethasone (VTD) with thalidomide plus doxorubicin and dexamethasone (TAD). Until now, first-line treatment with these combinations has not been reported in any comparative study. The principal objective of this study was to determine whether VTD would improve the complete response (CR) and CR plus very good partial response rates compared with TAD. Second, using additional methods, such as flow cytometric assays and polymerase chain reaction technology, we evaluated the molecular residual disease in the subgroup of patients that obtained CR. Our study shows that VTD is a superior induction regimen compared with TAD, with a higher response rate after induction, translating into greater CR plus very good partial response.
No preview · Article · Oct 2012 · Acta Haematologica
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.
Full-text · Article · May 2012 · British Journal of Haematology
[Show abstract][Hide abstract] ABSTRACT: Cytokines play a central role in multiple myeloma (MM) pathogenesis thus genetic variations within cytokines coding genes could influence MM susceptibility and therapy outcome. We investigated the impact of 8 SNPs in these genes in 202 MM cases and 235 controls also evaluating their impact on therapy outcome in a subset of 91 patients. Despite the overall negative findings, we found a significant age-modified effect of IL6 and TNF-α SNPs, on MM risk and therapy outcome, respectively. Therefore, this observation suggests that genetic variation in inflammation-related genes could be an important mediator of the complex interplay between ageing and cancer.
No preview · Article · Mar 2012 · Leukemia research