Person: Real Arribas, Francisco
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Francisco
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Real Arribas
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CNIO
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Publication A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.(BioMed Central (BMC), 2021-02-01) López de Maturana, Evangelina; Rodríguez, Juan Antonio; Alonso, Lola; Lao, Oscar; Molina-Montes, Esther; Martín-Antoniano, Isabel Adoración; Gómez-Rubio, Paulina; Lawlor, Rita; Carrato, Alfredo; Hidalgo, Manuel; Iglesias, Mar; Molero, Xavier; Löhr, Matthias; Michalski, Christopher; Perea, José; O'Rorke, Michael; Barberà, Victor Manuel; Tardón, Adonina; Farré, Antoni; Muñoz-Bellvís, Luís; Crnogorac-Jurcevic, Tanja; Domínguez-Muñoz, Enrique; Gress, Thomas; Greenhalf, William; Sharp, Linda; Arnes, Luís; Cecchini, Lluís; Balsells, Joaquim; Costello, Eithne; Ilzarbe, Lucas; Kleeff, Jörg; Kong, Bo; Márquez, Mirari; Mora, Josefina; O'Driscoll, Damian; Scarpa, Aldo; Ye, Weimin; Yu, Jingru; García-Closas, Montserrat; Kogevinas, Manolis; Rothman, Nathaniel; Silverman, Debra T; Albanes, Demetrius; Arslan, Alan A; Beane-Freeman, Laura; Bracci, Paige M; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie; Canzian, Federico; Du, Margaret; Gallinger, Steve; Gaziano, J Michael; Goodman, Phyllis J; Gunter, Marc; LeMarchand, Loic; Li, Donghui; Neale, Rachael E; Peters, Ulrika; Petersen, Gloria M; Risch, Harvey A; Sánchez, Maria José; Shu, Xiao-Ou; Thornquist, Mark D; Visvanathan, Kala; Zheng, Wei; Chanock, Stephen J; Easton, Douglas; Wolpin, Brian M; Stolzenberg-Solomon, Rachael Z; Klein, Alison P; Amundadottir, Laufey T; Marti-Renom, Marc A; Real Arribas, Francisco; Malats, Nuria; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Unión Europea. European Cooperation in Science and Technology (COST).; Unión Europea; NIH - National Cancer Institute (NCI) (Estados Unidos)BACKGROUND Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.Publication Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis.(Public Library of Science (PLOS), 2014-05-12) Pineda, Silvia; Milne, Roger L; Calle, M Luz; Rothman, Nathaniel; Herranz, Jesús; Kogevinas, Manolis; Chanock, Stephen J; Tardón, Adonina; Márquez, Mirari; Guey, Lin T; García-Closas, Montserrat; Lloreta, Josep; Baum, Erin; Carrato, Alfredo; Navarro, Arcadi; Silverman, Debra T; Lopez de Maturana, Evangelina; Malats, Nuria; Gonzalez Neira, Anna; Real Arribas, Francisco; Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España); Fundación La Marató TV3; Unión Europea; United States Department of Health and Human Services; Institució Catalana de Recerca i Estudis AvançatsGermline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro), still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk. We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression analysis to assess multiple SNPs simultaneously. Based on classical analyses, SNPs in BAK1 (1), IGF1R (5), P53AIP1 (1), PMAIP1 (2), SERINPB5 (3), TP63 (3), and TP73 (1) showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8). LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation. We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.Publication A faecal microbiota signature with high specificity for pancreatic cancer.(BMJ Publishing Group, 2022-03-08) Kartal, Ece; Schmidt, Thomas S B; Wirbel, Jakob; Maistrenko, Oleksandr M; Akanni, Wasiu A; Alashkar Alhamwe, Bilal; Alves, Renato J; Carrato, Alfredo; Erasmus, Hans-Peter; Estudillo, Lidia; Finkelmeier, Fabian; Fullam, Anthony; Glazek, Anna M; Gómez-Rubio, Paulina; Hercog, Rajna; Jung, Ferris; Kandels, Stefanie; Kersting, Stephan; Langheinrich, Melanie; Márquez, Mirari; Molero, Xavier; Orakov, Askarbek; Van Rossum, Thea; Raul, Torres-Ruiz; Telzerow, Anja; Zych, Konrad; Benes, Vladimir; Zeller, Georg; Trebicka, Jonel; Bork, Peer; Malats, Nuria; Molina-Montes, Esther; Rodriguez Perales, Sandra; Real Arribas, Francisco; World Cancer Research Fund International; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Federal Ministry of Education & Research (Alemania); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España)Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. To explore the faecal and salivary microbiota as potential diagnostic biomarkers. We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.Publication Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.(Wiley, 2018-02-01) Rava, Marta; Czachorowski, Maciej J; Silverman, Debra; Márquez, Mirari; Kishore, Sirish; Tardón, Adonina; Serra, Consol; García-Closas, Montse; Garcia-Closas, Reina; Carrato, Alfredo; Rothman, Nathaniel; Kogevinas, Manolis; Malats, Nuria; Real Arribas, Francisco; Asociación Española Contra el Cáncer; NIH - National Cancer Institute (NCI) (Estados Unidos); Instituto de Salud Carlos III; United States Department of Health and Human Services; Unión EuropeaPrevious studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis.Publication Risk prediction scores for recurrence and progression of non-muscle invasive bladder cancer: an international validation in primary tumours.(Public Library of Science (PLOS), 2014-06-06) Vedder, Moniek M; Márquez, Mirari; de Bekker-Grob, Esther W; Calle, Malu L; Dyrskjøt, Lars; Kogevinas, Manoils; Segersten, Ulrika; Malmström, Per-Uno; Algaba, Ferran; Beukers, Willemien; Ørntoft, Torben F; Zwarthoff, Ellen; Steyerberg, Ewout W; Real Arribas, Francisco; Malats, Nuria; Unión Europea; Danish Cancer SocietyWe aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours. We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability. The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p<0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10-year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61. The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.