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Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

Contains fulltext : 232394.pdf (Publisher’s version ) (Closed access) We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL., Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival., Univerity of Pisa, Helmholtz Association, Instituto de Salud Carlos III PI12/02688 PI17/02276, Instituto de Salud Carlos III, European Commission, FEDER funds-a way to build Europe PI14-00613, Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723, Projekt DEAL

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival., Partially supported by intramural funds of DKFZ, by grants PI12/02688 and PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grant PI14-00613 and Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany) and the Saarland Ministry of Social Affairs, Health, Women and Family (Saarbrücken, Germany)

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p

Se ha llevado a cabo un estudio cuantitativo de microfotografías electrónicas de 3 placentas de Cerro de Pasco (altura, 4,330 m.), 4 placentas de Puno (3,850 m.) y 4 placentas de Lima (150 m.). Se ha determinado que el área de la superficie villosa determinada por el microscopio de luz se incrementa, debido a la presencia de microvillos por un factor de 5.23 en Cerro de Pasco, 3.50 en Puno y 3.03 en Lima (valores medios). Como resultado, el área de intercambio materno-fetal es de 60.72 m2 en Cerro de Pasco, 38.92 m2 en Puno y 26.60 m2 en Lima. El hallazgo se interpreta como un mecanismo adaptativo de la placenta de altura a la situación de hipoxia, para favorecer los fenómenos de intercambio materno-fetal. Mediciones lineales simples del grosor de la barrera placentaria no mostraron diferencias entre los grupos de altura y de nivel del mar. Debido al carácter relativo de la medición no se descartan, diferencias reales con otro tipo de medición. No se observaron diferencias en la composición citológica y en las características ultraestructurales generales de la barrera materno-fetal en la altura y a nivel del mar. Sin embargo, no se descarta la posibilidad de diferencias en el número, forma y tamaño de las organelas celulares.

Los autores han estudiado peso de recién nacidos y placentas de embarazos de Puno, Perú, a una altitud de 3.850 m .; se han estudiado 46 embarazos normales de diferentes hospitales desde 46 grupo control normaI que Lima a 150 m. Los pesos de los recién nacidos fueron similares en ambos lugares, sin embargo, el peso de la placenta y el volumen fueron mayores en Puno, por lo que el coeficiente de la placenta fue mayor en altura. El análisis macroscópico en términos de parénquima y tejido no parénquima no fue diferente en ambos grupos, pero el análisis microscópico mostró capilaridad más rica con vellosidades disminuido en Puno. No se apreciaron diferencias en la proporción de ephithelium trofoblástica. El área total de la superficie de las vellosidades y capilar corial fueron significativamente mayor en altura. Los autores postulan estos cambios morfológicos favorecen el intercambio placentario metabólica en el ambiente hipóxico de gran altura.

Myelodysplastic syndromes (MDS) often transform into acute leukemia (AL-MDS), although its prognostic details have not been examined thoroughly. We retrospectively analyzed the prognosis of 189 AL-MDS patients. Ninety-four patients received best supportive care (BSC), and 94 patients received disease-modifying therapies (DMT) that included chemotherapy (CHT) for 65 patients, allogeneic stem-cell transplantation (allo-SCT) for 21 patients, and other therapies for 8 patients. The median survival time was 142 days. In patients treated with BSC, platelet count alone was an independent prognostic factor. In younger patients treated with DMT (

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Multiple myeloma (MM) is a heterogeneous disease group regarding prognosis, clinical course, and response to therapeutic interventions. Numerous prognostic factors have been identified however there was no consensus about the best prognostic indicators or the proper staging systems. In a previous study the A/M ratio containing albumin (A) and monoclonal component (M) emerged as reliable predictor of survival duration in patients treated with conventional chemotherapy. In the current retrospective study authors evaluated the prognostic role of this fraction in the era of novel agents. They assessed the A/M ratio prior treatment in 56 newly diagnosed MM patients from the aspect of the survival time. According to the results the A/M being

Allelic distribution of −308 G > A (TNF 1/2) polymorphism of the TNF-alpha, and the +252 A > G promoter polymorphism of the LT-alpha gene, the 1267 A > G polymorphism of the HSP70-2 gene as well as the −429 T > C promoter polymorphism of the RAGE gene were tested in 94 MM cases and 141 controls. Significantly less MM patients than controls carried the TNF2 allele (p = 0.018) and the TNF2-LTA 252G haplotype (p = 0.025). The difference was, however, restricted to the females, as well as the relatively young (