Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in this study. We conducted a multi-phase study analysing 7,745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14,666 PDAC cases and 221,897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR=1.11, 95%CI=1.07-1.15, P=5.25×10-9 ). CDKN2B-AS1/ANRIL is a long non-coding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases. This article is protected by copyright. All rights reserved

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case control study comprising four different populations, for a total of 14,538 PDAC cases and 190,657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P=2.46x10 -9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P=1.53x10 -6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of GWAS studies in light of functional data

Green and scalable synthesis of nanocrystalline kuramite

The new generation of solar cells aims to overcome many of the issues created by silicon-based devices (e.g., decommissioning, flexibility and high-energy production costs). Due to the scarcity of the resources involved in the process and the need for the reduction of potential pollution, a greener approach to solar cell material production is required. Among others, the solvothermal approach for the synthesis of nanocrystalline Cu-Sn-S (CTS) materials fulfils all of these requirements. The material constraints must be considered, not only for the final product, but for the whole production process. Most works reporting the successful synthesis of CTS have employed surfactants, high pressure or noxious solvents. In this paper, we demonstrate the synthesis of nanocrystalline kuramite by means of a simpler, greener and scalable solvothermal synthesis. We exploited a multianalytical characterization approach (X-ray diffraction, extended X-ray absorption fine structure, field emission scanning electron microscopy, Raman spectroscopy and electronic microprobe analysis (EMPA) to discriminate kuramite from other closely related polymorphs. Moreover, we confirmed the presence of structural defects due to a relevant antisite population

Genetically determined telomere length and multiple myeloma risk and outcome

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 PisaHelmholtz AssociationInstituto de Salud Carlos III PI12/02688 PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723Projekt DEA

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10−8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10−7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10−6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10−5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.</p

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10−8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10−7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10−6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10−5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.</p

Analisi dell'associazione tra la lunghezza dei telomeri geneticamente determinata ed il rischio di sviluppare il mieloma multiplo.

Il mieloma multiplo (MM) è una neoplasia incurabile delle plasmacellule. Due studi hanno messo in evidenza un’associazione tra il rischio di sviluppo di MM e telomeri più lunghi, tuttavia il limite principale di queste analisi è la misurazione sperimentale dei telomeri poiché essa è prona a molti errori tecnici e che riguardano il disegno dello studio. Mediante Genome-Wide Association Studies (GWAS), sono emersi diversi polimorfismi a singolo nucleotide (SNPs) associati alla variazione della lunghezza dei telomeri. Lo scopo dello studio è stato verificare se fosse possibile utilizzare questi SNPs, combinati in uno score chiamato “teloscore”, per valutare l’associazione con il rischio di MM. Sono stati selezionati 11 SNPs e sono stati genotipizzati 1741 controlli e 2407 casi di MM nel contesto dell’International Multiple Myeloma (IMMeNSE) consortium. Dall’analisi di rischio è stata trovata una nuova associazione tra il MM e lo SNP OBFC1-rs9420907: ORhet=1.32 (95% CI 1.22 – 1.55), Pvalue=7.78x10-4, oltre ad essere stata confermata l’associazione con TERC-rs10936599, di cui era già nota la relazione con il MM. Dall’analisi del teloscore, è stato osservato un incremento del rischio di MM all’aumentare della lunghezza dei telomeri: OR=1.84 (95%CI 1.47-2.30), P=5.98x10-8, confrontando il maggiore con il minore dei quintili dello score). Dallo studio effettuato si evince che telomeri lunghi geneticamente possano essere un marcatore di rischio per lo sviluppo del mieloma multiplo

Genetic and genomic susceptibility of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a neoplasm characterized by a high mortality rate due to the absence of specific symptoms, diagnostic markers for early detection and efficient therapies. The identification of high-risk individuals genetically predisposed to PDAC development may improve the diagnosis at early stages of the disease. So far, common genetic variants and high penetrance mutations have been associated to PDAC risk, but PDAC genetic architecture has been only partially discovered. In this Ph.D. project, to identify novel low-frequency and rare variants associated with PDAC risk, a fine mapping of known PDAC risk loci has been conducted through the sequencing of 480 PDAC patients. In addition, the genotypes and the summary statistics from genome-wide association studies conducted on PDAC risk were used to perform case-control association studies based on biological hypothesis. Through this approach, called secondary analysis, 127,887 common variants were analysed in 20,320 PDAC cases and 225,365 controls. The fine mapping approach showed eight pathogenic genetic variants with a frequency of alternative alleles higher than what reported. In particular, the most interesting variant is MSH2-rs193922376-T that was already associated with Lynch syndrome, that has several clinical manifestations among which PDAC. Secondary analyses identified three novel susceptibility loci for PDAC: rs1412832-T (P=5.25×10-9) in the long non-coding gene CDKN2B-AS1 and two missense rs9581957-C (P=2.46x10-9) and rs2277598-T (P=1.53x10-6) in URAD and BBS4, respectively. In conclusion, in our study we identified several common, low-frequency and rare genetic variants that could be used in future screening programs of PDAC high-risk individuals

Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms

D.C., F.C., and M.G. conceived and designed the study. A.M. and M.G. performed labwork. A.M., F.C., D.C., and M.G. drafted the manuscript. A.M., F.C., D.C., and M.G. performed data quality control and statistical analyses. All other authors provided samples and data. All authors critically read, commented, and approved the manuscript.Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the “teloscore” in 480 MPN patients and 909 healthy controls in a European multi-center case–control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24–2.68, P = 2.21 × 10−3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic= 1.43; 95% CI 1.15–1.77; P = 1.35 × 10−3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN developmen

Genome-wide association study of mitochondrial copy number

: Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait