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1. Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome

Author: Matteo Giaccherini, Alyssa I. Clay-Gilmour, Romano Liotti, Angelica Macauda, Manuel Gentiluomo, Elizabeth E. Brown, Mitchell J. Machiela, Stephen J. Chanock, Michelle A. T. Hildebrandt, Aaron D. Norman, Elisabet Manasanch, S. Vincent Rajkumar, Jonathan N. Hofmann, Sonja I. Berndt, Parveen Bhatti, Graham G. Giles, Elad Ziv, Shaji K. Kumar, Nicola J. Camp, Wendy Cozen, Susan L. Slager, Federico Canzian, Federica Gemignani, Celine M. Vachon, and Daniele Campa
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2024
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2. Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study

Author: Neil Daniel, Riccardo Farinella, Anastasia Chrysovalantou Chatziioannou, Mazda Jenab, Ana-Lucia Mayén, Cosmeri Rizzato, Flavia Belluomini, Federico Canzian, Arianna Tavanti, Pekka Keski-Rahkonen, David J. Hughes, and Daniele Campa
Subjects: Mendelian randomisation, Gut microbiome, Bacteria-related metabolites, Pancreatic ductal adenocarcinoma, Medicine, Science
Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.
Published: 2024
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3. Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Author: Pelin Ünal, Ye Lu, Bas Bueno-de-Mesquita, Casper H. J. van Eijck, Renata Talar-Wojnarowska, Andrea Szentesi, Maria Gazouli, Edita Kreivenaite, Francesca Tavano, Ewa Małecka-Wojciesko, Bálint Erőss, Martin Oliverius, Stefania Bunduc, Mateus Nóbrega Aoki, Ludmila Vodickova, Ugo Boggi, Matteo Giaccherini, Jurate Kondrackiene, Roger Chammas, Orazio Palmieri, George E. Theodoropoulos, Maarten F. Bijlsma, Daniela Basso, Beatrice Mohelnikova-Duchonova, Pavel Soucek, Jakob R. Izbicki, Vytautas Kiudelis, Giuseppe Vanella, Paolo Giorgio Arcidiacono, Barbara Włodarczyk, Thilo Hackert, Ben Schöttker, Faik G. Uzunoglu, Franco Bambi, Mara Goetz, Viktor Hlavac, Hermann Brenner, Francesco Perri, Silvia Carrara, Stefano Landi, Péter Hegyi, Frederike Dijk, Evaristo Maiello, Giovanni Capretti, Sabrina Gloria Giulia Testoni, Maria Chiara Petrone, Hannah Stocker, Stefano Ermini, Livia Archibugi, Manuel Gentiluomo, Giulia Martina Cavestro, Raffaele Pezzilli, Gregorio Di Franco, Anna Caterina Milanetto, Cosimo Sperti, John P. Neoptolemos, Luca Morelli, Klara Vokacova, Claudio Pasquali, Rita T. Lawlor, Francesca Bazzocchi, Juozas Kupcinskas, Gabriele Capurso, Daniele Campa, and Federico Canzian
Subjects: Association study, Enhancer, Pancreatic cancer, Single nucleotide polymorphism, Transcription factor binding site, Medicine, Genetics, QH426-470
Abstract: Abstract 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.
Published: 2024
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4. Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Author: Margherita Piccardi, Manuel Gentiluomo, Stefania Bertoncini, Raffaele Pezzilli, Bálint Erőss, Stefania Bunduc, Faik G. Uzunoglu, Renata Talar-Wojnarowska, Tomas Vanagas, Cosimo Sperti, Martin Oliverius, Mateus Nóbrega Aoki, Stefano Ermini, Tamás Hussein, Ugo Boggi, Krzysztof Jamroziak, Evaristo Maiello, Luca Morelli, Ludmila Vodickova, Gregorio Di Franco, Stefano Landi, Andrea Szentesi, Martin Lovecek, Marta Puzzono, Francesca Tavano, Hanneke W. M. van Laarhoven, Alessandro Zerbi, Beatrice Mohelnikova-Duchonova, Hannah Stocker, Eithne Costello, Gabriele Capurso, Laura Ginocchi, Rita T. Lawlor, Giuseppe Vanella, Francesca Bazzocchi, Jakob R. Izbicki, Anna Latiano, Bas Bueno-de-Mesquita, Ruggero Ponz de Leon Pisani, Ben Schöttker, Pavel Soucek, Péter Hegyi, Maria Gazouli, Thilo Hackert, Juozas Kupcinskas, Lina Poskiene, Matteo Tacelli, Susanne Roth, Silvia Carrara, Francesco Perri, Viktor Hlavac, George E. Theodoropoulos, Olivier R. Busch, Andrea Mambrini, Casper H. J. van Eijck, Paolo Arcidiacono, Aldo Scarpa, Claudio Pasquali, Daniela Basso, Maurizio Lucchesi, Anna Caterina Milanetto, John P. Neoptolemos, Giulia Martina Cavestro, Dainius Janciauskas, Xuechen Chen, Roger Chammas, Mara Goetz, Hermann Brenner, Livia Archibugi, Michael Dannemann, Federico Canzian, Sergio Tofanelli, and Daniele Campa
Subjects: Neandertal, Pancreatic cancer, Association study, Introgression, Eurasians, Admixture, Biology (General), QH301-705.5
Abstract: Abstract Background The genomes of present-day non-Africans are composed of 1–3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50–60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. Results The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19–1.54, P = 3.59 × 10–6), with a P-value close to a threshold that takes into account multiple testing. Conclusions Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.
Published: 2023
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5. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author: Pooja Middha, Xiaoliang Wang, Sabine Behrens, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Thaïs Baert, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Javier Benitez, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Daniele Campa, Federico Canzian, Angel Carracedo, Jose E. Castelao, Stephen J. Chanock, Georgia Chenevix-Trench, CTS Consortium, Emilie Cordina-Duverger, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Laure Dossus, Pierre-Antoine Dugué, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Graham G. Giles, Anna González-Neira, Felix Grassmann, Anne Grundy, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Bernd Holleczek, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Christian Ingvar, ABCTB Investigators, kConFab Investigators, Karolin Isaksson, Helena Jernström, Esther M. John, Michael E. Jones, Rudolf Kaaks, Renske Keeman, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Susanna Larsson, Loic Le Marchand, Flavio Lejbkowicz, Shuai Li, Martha Linet, Jolanta Lissowska, Maria Elena Martinez, Tabea Maurer, Anna Marie Mulligan, Claire Mulot, Rachel A. Murphy, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Katie M. O’Brien, Janet E. Olson, Alpa V. Patel, Ross Prentice, Erika Rees-Punia, Gad Rennert, Valerie Rhenius, Kathryn J. Ruddy, Dale P. Sandler, Christopher G. Scott, Mitul Shah, Xiao-Ou Shu, Ann Smeets, Melissa C. Southey, Jennifer Stone, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Katarzyna Tomczyk, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Sophia S. Wang, Clarice R. Weinberg, Hans Wildiers, Walter Willett, Stacey J. Winham, Alicja Wolk, Xiaohong R. Yang, M. Pilar Zamora, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Paul D. P. Pharoah, Montserrat García-Closas, Marjanka K. Schmidt, Peter Kraft, Roger L. Milne, Sara Lindström, Douglas F. Easton, and Jenny Chang-Claude
Subjects: Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability
Published: 2023
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6. Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Author: Giulia Peduzzi, Livia Archibugi, Verena Katzke, Manuel Gentiluomo, Gabriele Capurso, Anna Caterina Milanetto, Maria Gazouli, Mara Goetz, Hermann Brenner, Roel C. H. Vermeulen, Renata Talar-Wojnarowska, Giuseppe Vanella, Francesca Tavano, Maurizio Lucchesi, Beatrice Mohelnikova-Duchonova, Xuechen Chen, Vytautas Kiudelis, Péter Hegyi, Martin Oliverius, Hannah Stocker, Caterina Stornello, Ludmila Vodickova, Pavel Souček, John P. Neoptolemos, Sabrina Gloria Giulia Testoni, Luca Morelli, Rita T. Lawlor, Daniela Basso, Jakob R. Izbicki, Stefano Ermini, Juozas Kupcinskas, Raffaele Pezzilli, Ugo Boggi, Hanneke W. M. van Laarhoven, Andrea Szentesi, Bálint Erőss, Giovanni Capretti, Ben Schöttker, Jurgita Skieceviciene, Mateus Nóbrega Aoki, Casper H. J. van Eijck, Giulia Martina Cavestro, Federico Canzian, and Daniele Campa
Subjects: Medicine, Science
Abstract: Abstract The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P
Published: 2022
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7. Role of pancreatic ductal adenocarcinoma risk factors in intraductal papillary mucinous neoplasm progression

Author: Manuel Gentiluomo, Chiara Corradi, Paolo Giorgio Arcidiacono, Stefano Crippa, Massimo Falconi, Giulio Belfiori, Riccardo Farinella, Laura Apadula, Gaetano Lauri, Niccolò Bina, Cosmeri Rizzato, Federico Canzian, Luca Morelli, Gabriele Capurso, and Daniele Campa
Subjects: pancreatic ductal adenocarcinoma (PADC), intraductal papillary mucinous neoplasms (IPMN), single nucleotide polymorphism (SNP), association study, polygenic score (PGS), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: IntroductionPancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is prevention. Intraductal papillary mucinous neoplasms (IPMNs) are precursors of PDAC. It is difficult to estimate the incidence of IPMNs because they are asymptomatic. Two recent studies reported pancreatic cysts in 3% and 13% of scanned subjects. The possibility of identifying a subgroup of IPMN patients with a higher probability of progression into cancer could be instrumental in increasing the survival rate. In this study, genetic and non-genetic PDAC risk factors were tested in a group of IPMN patients under surveillance.MethodsA retrospective study was conducted on 354 IPMN patients enrolled in two Italian centres with an average follow-up of 64 months. With the use of DNA extracted from blood, collected at IPMN diagnosis, all patients were genotyped for 30 known PDAC risk loci. The polymorphisms were analysed individually and grouped in an unweighted polygenic score (PGS) in relation to IPMN progression. The ABO blood group and non-genetic PDAC risk factors were also analysed. IPMN progression was defined based on the development of worrisome features and/or high-risk stigmata during follow-up.ResultsTwo genetic variants (rs1517037 and rs10094872) showed suggestive associations with an increment of IPMN progression. After correction for multiple testing, using the Bonferroni correction, none of the variants showed a statistically significant association. However, associations were observed for the non-genetic variables, such as smoking status, comparing heavy smokers with light smokers (HR = 3.81, 95% 1.43–10.09, p = 0.007), and obesity (HR = 2.46, 95% CI 1.22–4.95, p = 0.012).ConclusionIn conclusion, this study is the first attempt to investigate the presence of shared genetic background between PDAC risk and IPMN progression; however, the results suggest that the 30 established PDAC susceptibility polymorphisms are not associated with clinical IPMN progression in a sample of 354 patients. However, we observed indications of cigarette smoking and body mass index (BMI) involvement in IPMN progression. The biological mechanism that could link these two risk factors to progression could be chronic inflammation, of which both smoking and obesity are strong promoters.
Published: 2023
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8. Validation and functional characterization of GWAS-identified variants for chronic lymphocytic leukemia: a CRuCIAL study

Author: Paloma García-Martín, Ana Moñiz Díez, José Manuel Sánchez Maldonado, Antonio José Cabrera Serrano, Rob ter Horst, Yolanda Benavente, Stefano Landi, Angelica Macauda, Alyssa Clay-Gilmour, Francisca Hernández-Mohedo, Yasmeen Niazi, Pedro González-Sierra, Blanca Espinet, Juan José Rodríguez-Sevilla, Rossana Maffei, Gonzalo Blanco, Matteo Giaccherini, Anna Puiggros, James Cerhan, Roberto Marasca, Marisa Cañadas-Garre, Miguel Ángel López-Nevot, Tzu Chen-Liang, Hauke Thomsen, Irene Gámez, Víctor Moreno, Rafael Marcos-Gragera, María García-Álvarez, Javier Llorca, Andrés Jerez, Sonja Berndt, Aleksandra Butrym, Aaron D. Norman, Delphine Casabonne, Mario Luppi, Susan L. Slager, Kari Hemminki, Yang Li, Miguel Alcoceba, Daniele Campa, Federico Canzian, Silvia de Sanjosé, Asta Försti, Mihai G. Netea, Manuel Jurado, and Juan Sainz
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2022
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9. Maternal anthropometric variables and clinical factors shape neonatal microbiome

Author: Riccardo Farinella, Cosmeri Rizzato, Daria Bottai, Alice Bedini, Federica Gemignani, Stefano Landi, Giulia Peduzzi, Sara Rosati, Antonella Lupetti, Armando Cuttano, Francesca Moscuzza, Cristina Tuoni, Luca Filippi, Massimiliano Ciantelli, Arianna Tavanti, and Daniele Campa
Subjects: Medicine, Science
Abstract: Abstract Recent studies indicate the existence of a complex microbiome in the meconium of newborns that plays a key role in regulating many host health-related conditions. However, a high variability between studies has been observed so far. In the present study, the meconium microbiome composition and the predicted microbial metabolic pathways were analysed in a consecutive cohort of 96 full-term newborns. The effect of maternal epidemiological variables on meconium diversity was analysed using regression analysis and PERMANOVA. Meconium microbiome composition mainly included Proteobacteria (30.95%), Bacteroidetes (23.17%) and Firmicutes (17.13%), while for predicted metabolic pathways, the most abundant genes belonged to the class “metabolism”. We observed a significant effect of maternal Rh factor on Shannon and Inverse Simpson indexes (p = 0.045 and p = 0.049 respectively) and a significant effect of delivery mode and maternal antibiotic exposure on Jaccard and Bray–Curtis dissimilarities (p = 0.001 and 0.002 respectively), while gestational age was associated with observed richness and Shannon indexes (p = 0.018 and 0.037 respectively), and Jaccard and Bray–Curtis dissimilarities (p = 0.014 and 0.013 respectively). The association involving maternal Rh phenotype suggests a role for host genetics in shaping meconium microbiome prior to the exposition to the most well-known environmental variables, which will influence microbiome maturation in the newborn.
Published: 2022
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10. Impact of genetic polymorphisms of drug transporters ABCB1 and ABCG2 and regulators of xenobiotic transport and metabolism PXR and CAR on clinical efficacy of dasatinib in chronic myeloid leukemia

Author: Anna Marta Madejczyk, Federico Canzian, Joanna Góra-Tybor, Daniele Campa, Tomasz Sacha, Dorota Link-Lenczowska, Izabela Florek, Witold Prejzner, M. Całbecka, M. Rymko, M. Dudziński, Magdalena Julita Orzechowska, and Krzysztof Jamroziak
Subjects: Chronic myeloid leukemia, dasatinib, ABCB1, ABCG2, PXR, CAR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: IntroductionFunctional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2.Aim of the studyIn this study, we assessed the impact of inherited variants in ABCB1, ABCG2, PXR, and CAR genes on dasatinib efficacy and toxicity in CML.Materials and methodsSixty-one tagging SNPs in ABCB1, ABCG2, PXR, and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy.ResultsWe found the associations between SNPs rs7787082 (ABCB1, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (ABCG2, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (ABCG2, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1. Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1, rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model.ConclusionOur data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients.
Published: 2022
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11. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Anna Morra, Maria Escala-Garcia, Jonathan Beesley, Renske Keeman, Sander Canisius, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Thomas Brüning, Saundra S. Buys, Bette Caan, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Ting-Yuan David Cheng, Christine L. Clarke, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Thilo Dörk, Laure Dossus, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, José A. García-Sáenz, Graham G. Giles, Mervi Grip, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Jaana M. Hartikainen, Arndt Hartmann, Wei He, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, ABCTB Investigators, kConFab Investigators, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Machteld Keupers, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Martha Linet, Robert N. Luben, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Andrew F. Olshan, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Bernard Peissel, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Brigitte Rack, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiss, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Lauren R. Teras, Mary Beth Terry, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Amber N. Hurson, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, Hiltrud Brauch, Montserrat García-Closas, Paul D. P. Pharoah, Douglas F. Easton, Georgia Chenevix-Trench, and Marjanka K. Schmidt
Subjects: Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP
Published: 2021
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12. Genetically determined telomere length and multiple myeloma risk and outcome

Author: Matteo Giaccherini, Angelica Macauda, Enrico Orciuolo, Marcin Rymko, Karolina Gruenpeter, Charles Dumontet, Malgorzata Raźny, Victor Moreno, Gabriele Buda, Katia Beider, Judit Varkonyi, Hervé Avet-Loiseau, Joaquín Martinez-Lopez, Herlander Marques, Marzena Watek, Maria Eugenia Sarasquete, Vibeke Andersen, Lionel Karlin, Anna Suska, Marcin Kruszewski, Niels Abildgaard, Marek Dudziński, Aleksandra Butrym, Arnold Nagler, Annette Juul Vangsted, Katalin Kadar, Tomczak Waldemar, Krzysztof Jamroziak, Svend Erik Hove Jacobsen, Lene Hyldahl Ebbesen, Michał Taszner, Grzegorz Mazur, Fabienne Lesueur, Matteo Pelosini, Ramon Garcia-Sanz, Artur Jurczyszyn, Delphine Demangel, Rui Manuel Reis, Elżbieta Iskierka-Jażdżewska, Miroslaw Markiewicz, Federica Gemignani, Edyta Subocz, Daria Zawirska, Agnieszka Druzd-Sitek, Anna Stępień, M. Henar Alonso, Juan Sainz, Federico Canzian, and Daniele Campa
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract 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 × 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.
Published: 2021
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13. Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival

Author: Manuel Gentiluomo, Chiara Corradi, Giuseppe Vanella, Astrid Z. Johansen, Oliver Strobel, Andrea Szentesi, Anna Caterina Milanetto, Péter Hegyi, Juozas Kupcinskas, Francesca Tavano, John P. Neoptolemos, Dania Bozzato, Thilo Hackert, Raffaele Pezzilli, Julia S. Johansen, Eithne Costello, Beatrice Mohelnikova-Duchonova, Casper H. J. van Eijck, Renata Talar-Wojnarowska, Carsten Palnæs Hansen, Erika Darvasi, Inna M. Chen, Giulia Martina Cavestro, Pavel Soucek, Liliana Piredda, Pavel Vodicka, Maria Gazouli, Paolo Giorgio Arcidiacono, Federico Canzian, Daniele Campa, and Gabriele Capurso
Subjects: Medicine, Science
Abstract: Abstract Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients’ response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58–15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.
Published: 2021
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14. Polymorphic variants in Sweet and Umami taste receptor genes and birthweight

Author: Riccardo Farinella, Ilaria Erbi, Alice Bedini, Sara Donato, Manuel Gentiluomo, Claudia Angelucci, Antonella Lupetti, Armando Cuttano, Francesca Moscuzza, Cristina Tuoni, Cosmeri Rizzato, Massimiliano Ciantelli, and Daniele Campa
Subjects: Medicine, Science
Abstract: Abstract The first thousand days of life from conception have a significant impact on the health status with short, and long-term effects. Among several anthropometric and maternal lifestyle parameters birth weight plays a crucial role on the growth and neurological development of infants. Recent genome wide association studies (GWAS) have demonstrated a robust foetal and maternal genetic background of birth weight, however only a small proportion of the genetic hereditability has been already identified. Considering the extensive number of phenotypes on which they are involved, we focused on identifying the possible effect of genetic variants belonging to taste receptor genes and birthweight. In the human genome there are two taste receptors family the bitter receptors (TAS2Rs) and the sweet and umami receptors (TAS1Rs). In particular sweet perception is due to a heterodimeric receptor encoded by the TAS1R2 and the TAS1R3 gene, while the umami taste receptor is encoded by the TAS1R1 and the TAS1R3 genes. We observed that carriers of the T allele of the TAS1R1-rs4908932 SNPs showed an increase in birthweight compared to GG homozygotes Coeff: 87.40 (35.13–139.68) p-value = 0.001. The association remained significant after correction for multiple testing. TAS1R1-rs4908932 is a potentially functional SNP and is in linkage disequilibrium with another polymorphism that has been associated with BMI in adults showing the importance of this variant from the early stages of conception through all the adult life.
Published: 2021
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15. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021
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16. Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

Author: Ye Lu, Manuel Gentiluomo, Angelica Macauda, Domenica Gioffreda, Maria Gazouli, Maria C. Petrone, Dezső Kelemen, Laura Ginocchi, Luca Morelli, Konstantinos Papiris, William Greenhalf, Jakob R. Izbicki, Vytautas Kiudelis, Beatrice Mohelníková-Duchoňová, Bas Bueno-de-Mesquita, Pavel Vodicka, Hermann Brenner, Markus K. Diener, Raffaele Pezzilli, Audrius Ivanauskas, Roberto Salvia, Andrea Szentesi, Mateus Nóbrega Aoki, Balázs C. Németh, Cosimo Sperti, Krzysztof Jamroziak, Roger Chammas, Martin Oliverius, Livia Archibugi, Stefano Ermini, János Novák, Juozas Kupcinskas, Ondřej Strouhal, Pavel Souček, Giulia M. Cavestro, Anna C. Milanetto, Giuseppe Vanella, John P. Neoptolemos, George E. Theodoropoulos, Hanneke W. M. van Laarhoven, Andrea Mambrini, Stefania Moz, Zdenek Kala, Martin Loveček, Daniela Basso, Faik G. Uzunoglu, Thilo Hackert, Sabrina G. G. Testoni, Viktor Hlaváč, Angelo Andriulli, Maurizio Lucchesi, Francesca Tavano, Silvia Carrara, Péter Hegyi, Paolo G. Arcidiacono, Olivier R. Busch, Rita T. Lawlor, Marta Puzzono, Ugo Boggi, Feng Guo, Ewa Małecka-Panas, Gabriele Capurso, Stefano Landi, Renata Talar-Wojnarowska, Oliver Strobel, Xin Gao, Yogesh Vashist, Daniele Campa, and Federico Canzian
Subjects: pancreatic cancer, susceptibility, genome-wide association study, recessive model, genetic polymorphisms, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.
Published: 2021
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17. Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Author: Ye Lu, Chiara Corradi, Manuel Gentiluomo, Evangelina López de Maturana, George E. Theodoropoulos, Susanne Roth, Evaristo Maiello, Luca Morelli, Livia Archibugi, Jakob R. Izbicki, Patricia Sarlós, Vytautas Kiudelis, Martin Oliverius, Mateus Nóbrega Aoki, Yogesh Vashist, Casper H. J. van Eijck, Maria Gazouli, Renata Talar-Wojnarowska, Andrea Mambrini, Raffaele Pezzilli, Bas Bueno-de-Mesquita, Péter Hegyi, Pavel Souček, John P. Neoptolemos, Gregorio Di Franco, Cosimo Sperti, Emanuele F. Kauffmann, Viktor Hlaváč, Faik G. Uzunoğlu, Stefano Ermini, Ewa Małecka-Panas, Maurizio Lucchesi, Giuseppe Vanella, Frederike Dijk, Beatrice Mohelníková-Duchoňová, Franco Bambi, Maria Chiara Petrone, Krzysztof Jamroziak, Feng Guo, Katerina Kolarova, Giovanni Capretti, Anna Caterina Milanetto, Laura Ginocchi, Martin Loveček, Marta Puzzono, Hanneke W. M. van Laarhoven, Silvia Carrara, Audrius Ivanauskas, Konstantinos Papiris, Daniela Basso, Paolo G. Arcidiacono, Ferenc Izbéki, Roger Chammas, Pavel Vodicka, Thilo Hackert, Claudio Pasquali, Maria L. Piredda, Eithne Costello-Goldring, Giulia Martina Cavestro, Andrea Szentesi, Francesca Tavano, Barbara Włodarczyk, Hermann Brenner, Edita Kreivenaite, Xin Gao, Stefania Bunduc, Roel C. H. Vermeulen, Martin A. Schneider, Anna Latiano, Domenica Gioffreda, Sabrina G. G. Testoni, Juozas Kupcinskas, Rita T. Lawlor, Gabriele Capurso, Núria Malats, Daniele Campa, and Federico Canzian
Subjects: pancreatic cancer, miRNA, genetic polymorphisms, susceptibility, pancreatic ductal adenocarcinoma, Genetics, QH426-470
Abstract: Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
Published: 2021
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18. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019
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19. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, and Georgia Chenevix-Trench
Subjects: Science
Abstract: Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.
Published: 2019
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20. Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.
Published: 2019
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21. Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Author: Daniele Campa, Myrto Barrdahl, Aurelia Santoro, Gianluca Severi, Laura Baglietto, Hanane Omichessan, Rosario Tumino, H. B(as). Bueno-de-Mesquita, Petra H. Peeters, Elisabete Weiderpass, Maria-Dolores Chirlaque, Miguel Rodríguez-Barranco, Antonio Agudo, Marc Gunter, Laure Dossus, Vittorio Krogh, Giuseppe Matullo, Antonia Trichopoulou, Ruth C. Travis, Federico Canzian, and Rudolf Kaaks
Subjects: Mitochondrial copy number, Telomere length, Breast cancer, Cancer epidemiology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC). Methods To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years. Results According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58–4.65, p = 3.07 × 10− 4 for highest vs. lowest quartile; OR 3.20, 95% CI 1.57–6.55, p = 1.41 × 10− 3 as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05–5.80, p = 0.04 for highest vs. lowest quartile). Conclusions We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.
Published: 2018
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22. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author: Alison P. Klein, Brian M. Wolpin, Harvey A. Risch, Rachael Z. Stolzenberg-Solomon, Evelina Mocci, Mingfeng Zhang, Federico Canzian, Erica J. Childs, Jason W. Hoskins, Ashley Jermusyk, Jun Zhong, Fei Chen, Demetrius Albanes, Gabriella Andreotti, Alan A. Arslan, Ana Babic, William R. Bamlet, Laura Beane-Freeman, Sonja I. Berndt, Amanda Blackford, Michael Borges, Ayelet Borgida, Paige M. Bracci, Lauren Brais, Paul Brennan, Hermann Brenner, Bas Bueno-de-Mesquita, Julie Buring, Daniele Campa, Gabriele Capurso, Giulia Martina Cavestro, Kari G. Chaffee, Charles C. Chung, Sean Cleary, Michelle Cotterchio, Frederike Dijk, Eric J. Duell, Lenka Foretova, Charles Fuchs, Niccola Funel, Steven Gallinger, J. Michael M. Gaziano, Maria Gazouli, Graham G. Giles, Edward Giovannucci, Michael Goggins, Gary E. Goodman, Phyllis J. Goodman, Thilo Hackert, Christopher Haiman, Patricia Hartge, Manal Hasan, Peter Hegyi, Kathy J. Helzlsouer, Joseph Herman, Ivana Holcatova, Elizabeth A. Holly, Robert Hoover, Rayjean J. Hung, Eric J. Jacobs, Krzysztof Jamroziak, Vladimir Janout, Rudolf Kaaks, Kay-Tee Khaw, Eric A. Klein, Manolis Kogevinas, Charles Kooperberg, Matthew H. Kulke, Juozas Kupcinskas, Robert J. Kurtz, Daniel Laheru, Stefano Landi, Rita T. Lawlor, I.-Min Lee, Loic LeMarchand, Lingeng Lu, Núria Malats, Andrea Mambrini, Satu Mannisto, Roger L. Milne, Beatrice Mohelníková-Duchoňová, Rachel E. Neale, John P. Neoptolemos, Ann L. Oberg, Sara H. Olson, Irene Orlow, Claudio Pasquali, Alpa V. Patel, Ulrike Peters, Raffaele Pezzilli, Miquel Porta, Francisco X. Real, Nathaniel Rothman, Ghislaine Scelo, Howard D. Sesso, Gianluca Severi, Xiao-Ou Shu, Debra Silverman, Jill P. Smith, Pavel Soucek, Malin Sund, Renata Talar-Wojnarowska, Francesca Tavano, Mark D. Thornquist, Geoffrey S. Tobias, Stephen K. Van Den Eeden, Yogesh Vashist, Kala Visvanathan, Pavel Vodicka, Jean Wactawski-Wende, Zhaoming Wang, Nicolas Wentzensen, Emily White, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Wei Zheng, Peter Kraft, Donghui Li, Stephen Chanock, Ofure Obazee, Gloria M. Petersen, and Laufey T. Amundadottir
Subjects: Science
Abstract: Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.
Published: 2018
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23. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4
Published: 2021
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24. Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer

Author: Jonathan Barontini, Marco Antinucci, Sergio Tofanelli, Maurizio Cammalleri, Massimo Dal Monte, Federica Gemignani, Pavel Vodicka, Roberto Marangoni, Ludmila Vodickova, Juozas Kupcinskas, Veronika Vymetalkova, Asta Forsti, Federico Canzian, Angelika Stein, Victor Moreno, Nicola Mastrodonato, Francesca Tavano, Anna Panza, Roberto Barale, Stefano Landi, and Daniele Campa
Subjects: Taste receptors, TAS2R16, Polymorphisms, Colon cancer, Rectal cancer, Colorectal cancer, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Abstract Background Genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. Methods We performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. Results We did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). Conclusions Our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts.
Published: 2017
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25. Association between taste receptor (TAS) genes and the perception of wine characteristics

Author: Maura Carrai, Daniele Campa, Pavel Vodicka, Riccardo Flamini, Irene Martelli, Jana Slyskova, Katerina Jiraskova, Alexandra Rejhova, Sona Vodenkova, Federico Canzian, Alberto Bertelli, Antonio Dalla Vedova, Luigi Bavaresco, Ludmila Vodickova, and Roberto Barale
Subjects: Medicine, Science
Abstract: Abstract Several studies have suggested a possible relationship between polymorphic variants of the taste receptors genes and the acceptance, liking and intake of food and beverages. In the last decade investigators have attempted to link the individual ability to taste 6-n-propylthiouracil (PROP) and the sensations, such as astringency and bitterness, elicited by wine or its components, but with contradictory results. We have used the genotype instead of the phenotype (responsiveness to PROP or other tastants), to test the possible relation between genetic variability and the perception of wine characteristic in 528 subjects from Italy and the Czech Republic. We observed several interesting associations, among which the association between several TAS2R38 gene single nucleotide polymorphisms (P = 0.002) and the TAS2R16-rs6466849 polymorphism with wine sourness P = 0.0003). These associations were consistent in both populations, even though the country of origin was an important factor in the two models, thus indicating therefore that genetics alongside cultural factors also play a significant role in the individual liking of wine.
Published: 2017
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26. Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium

Author: Jose Manuel Sánchez-Maldonado, Ana Moñiz-Díez, Rob ter Horst, Daniele Campa, Antonio José Cabrera-Serrano, Manuel Martínez-Bueno, María del Pilar Garrido-Collado, Francisca Hernández-Mohedo, Laura Fernández-Puerta, Miguel Ángel López-Nevot, Cristina Cunha, Pedro Antonio González-Sierra, Jan Springer, Michaela Lackner, Laura Alcazar-Fuoli, Luana Fianchi, José María Aguado, Livio Pagano, Elisa López-Fernández, Esther Clavero, Leonardo Potenza, Mario Luppi, Lucia Moratalla, Carlos Solano, Antonio Sampedro, Manuel Cuenca-Estrella, Cornelia Lass-Flörl, PCRAGA Study Group, Federico Canzian, Juergen Loeffler, Yang Li, Hermann Einsele, Mihai G. Netea, Lourdes Vázquez, Agostinho Carvalho, Manuel Jurado, and Juan Sainz
Subjects: invasive aspergillosis, TNFSF4, MAPKAPK2, genetic susceptibility, B cells, monocytes, Biology (General), QH301-705.5
Abstract: Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.
Published: 2020
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27. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author: Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W. Long, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Wei Zheng, Curtis A. Pettaway, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, Esther M. John, Adam B. Murphy, Lisa B. Signorello, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anslem J. M. Hennis, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, John S. Witte, Graham Casey, Sam Kaggwa, Michael B. Cook, Daniel O. Stram, William J. Blot, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E. Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K. Dieffenbach, Volker Arndt, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A. Clements, Manuel R. Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, The PRACTICAL consortium, David V. Conti, Demetrius Albanes, Christine Berg, Sonja I. Berndt, Daniele Campa, E. David Crawford, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward Giovannucci, Robert Hoover, David J. Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L. Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R. Schumacher, Alkes L. Price, Matthew L. Freedman, Christopher A. Haiman, and Bogdan Pasaniuc
Subjects: Science
Abstract: Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.
Published: 2016
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28. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Author: Edward J Saunders, Tokhir Dadaev, Daniel A Leongamornlert, Sarah Jugurnauth-Little, Malgorzata Tymrakiewicz, Fredrik Wiklund, Ali Amin Al Olama, Sara Benlloch, David E Neal, Freddie C Hamdy, Jenny L Donovan, Graham G Giles, Gianluca Severi, Henrik Gronberg, Markus Aly, Christopher A Haiman, Fredrick Schumacher, Brian E Henderson, Sara Lindstrom, Peter Kraft, David J Hunter, Susan Gapstur, Stephen Chanock, Sonja I Berndt, Demetrius Albanes, Gerald Andriole, Johanna Schleutker, Maren Weischer, Børge G Nordestgaard, Federico Canzian, Daniele Campa, Elio Riboli, Tim J Key, Ruth C Travis, Sue A Ingles, Esther M John, Richard B Hayes, Paul Pharoah, Kay-Tee Khaw, Janet L Stanford, Elaine A Ostrander, Lisa B Signorello, Stephen N Thibodeau, Daniel Schaid, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Judith A Clements, Manuel R Teixeira, Jianfeng Xu, Christos Mikropoulos, Chee Goh, Koveela Govindasami, Michelle Guy, Rosemary A Wilkinson, Emma J Sawyer, Angela Morgan, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, Douglas F Easton, Ken Muir, Rosalind A Eeles, and Zsofia Kote-Jarai
Subjects: Genetics, QH426-470
Abstract: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Published: 2014
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29. A genome-wide 'pleiotropy scan' does not identify new susceptibility loci for estrogen receptor negative breast cancer.

Author: Daniele Campa, Myrto Barrdahl, Konstantinos K Tsilidis, Gianluca Severi, W Ryan Diver, Afshan Siddiq, Stephen Chanock, Robert N Hoover, Regina G Ziegler, Christine D Berg, Saundra S Buys, Christopher A Haiman, Brian E Henderson, Fredrick R Schumacher, Loïc Le Marchand, Dieter Flesch-Janys, Sara Lindström, David J Hunter, Susan E Hankinson, Walter C Willett, Peter Kraft, David G Cox, Kay-Tee Khaw, Anne Tjønneland, Laure Dossus, Dimitrios Trichopoulos, Salvatore Panico, Carla H van Gils, Elisabete Weiderpass, Aurelio Barricarte, Malin Sund, Mia M Gaudet, Graham Giles, Melissa Southey, Laura Baglietto, Jenny Chang-Claude, Rudolf Kaaks, and Federico Canzian
Subjects: Medicine, Science
Abstract: Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P
Published: 2014
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30. Somatic mutations in exocrine pancreatic tumors: association with patient survival.

Author: P Sivaramakrishna Rachakonda, Andrea S Bauer, Huaping Xie, Daniele Campa, Cosmeri Rizzato, Federico Canzian, Stefania Beghelli, William Greenhalf, Eithne Costello, Michaela Schanne, Anette Heller, Aldo Scarpa, John P Neoptolemos, Jens Werner, Markus Büchler, Jörg D Hoheisel, Kari Hemminki, Nathalia Giese, and Rajiv Kumar
Subjects: Medicine, Science
Abstract: KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.
Published: 2013
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31. Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk.

Author: Mariana E De Araujo, Gertraud Erhart, Katharina Buck, Elisabeth Müller-Holzner, Michael Hubalek, Heidelinde Fiegl, Daniele Campa, Federico Canzian, Ursula Eilber, Jenny Chang-Claude, Stefan Coassin, Margot Haun, Lyudmyla Kedenko, Bernhard Paulweber, Roland Reitsamer, Irmgard Himmel, Dieter Flesch-Janys, Claudia Lamina, Florian Kronenberg, Lukas A Huber, and Anita Kloss-Brandstätter
Subjects: Medicine, Science
Abstract: BACKGROUND: The late endosomal LAMTOR complex serves as a convergence point for both the RAF/MEK/ERK and the PI3K/AKT/mTOR pathways. Interestingly, both of these signalling cascades play a significant role in the aetiology of breast cancer. Our aim was to address the possible role of genetic polymorphisms in LAMTOR2 and LAMTOR3 as genetic risk factors for breast cancer. METHODOLOGY/RESULTS: We sequenced the exons and exon-intron boundaries of LAMTOR2 (p14) and LAMTOR3 (MP1) in 50 prospectively collected pairs of cancerous tissue and blood samples from breast cancer patients and compared their genetic variability. We found one single nucleotide polymorphism (SNP) in LAMTOR2 (rs7541) and two SNPs in LAMTOR3 (rs2298735 and rs148972953) in both tumour and blood samples, but no somatic mutations in cancerous tissues. In addition, we genotyped all three SNPs in 296 samples from the Risk Prediction of Breast Cancer Metastasis Study and found evidence of a genetic association between rs148972953 and oestrogen (ER) and progesterone receptor negative status (PR) (ER: OR = 3.60 (1.15-11.28); PR: OR = 4.27 (1.43-12.72)). However, when we additionally genotyped rs148972953 in the MARIE study including 2,715 breast cancer cases and 5,216 controls, we observed neither a difference in genotype frequencies between patients and controls nor was the SNP associated with ER or PR. Finally, all three SNPs were equally frequent in breast cancer samples and female participants (n = 640) of the population-based SAPHIR Study. CONCLUSIONS: The identified polymorphisms in LAMTOR2 and LAMTOR3 do not seem to play a relevant role in breast cancer. Our work does not exclude a role of other not yet identified SNPs or that the here annotated polymorphism may in fact play a relevant role in other diseases. Our results underscore the importance of replication in association studies.
Published: 2013
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32. A comprehensive investigation on common polymorphisms in the MDR1/ABCB1 transporter gene and susceptibility to colorectal cancer.

Author: Daniele Campa, Juan Sainz, Barbara Pardini, Ludmila Vodickova, Alessio Naccarati, Anja Rudolph, Jan Novotny, Asta Försti, Stephan Buch, Witigo von Schönfels, Clemens Schafmayer, Henry Völzke, Michael Hoffmeister, Bernd Frank, Roberto Barale, Kari Hemminki, Jochen Hampe, Jenny Chang-Claude, Hermann Brenner, Pavel Vodicka, and Federico Canzian
Subjects: Medicine, Science
Abstract: ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P(trend) = 0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P(trend) = 0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.
Published: 2012
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33. Bitter taste receptor polymorphisms and human aging.

Author: Daniele Campa, Francesco De Rango, Maura Carrai, Paolina Crocco, Alberto Montesanto, Federico Canzian, Giuseppina Rose, Cosmeri Rizzato, Giuseppe Passarino, and Roberto Barale
Subjects: Medicine, Science
Abstract: Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics.
Published: 2012
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34. Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3.

Author: Sara Lindstrom, Fredrick Schumacher, Afshan Siddiq, Ruth C Travis, Daniele Campa, Sonja I Berndt, W Ryan Diver, Gianluca Severi, Naomi Allen, Gerald Andriole, Bas Bueno-de-Mesquita, Stephen J Chanock, David Crawford, J Michael Gaziano, Graham G Giles, Edward Giovannucci, Carolyn Guo, Christopher A Haiman, Richard B Hayes, Jytte Halkjaer, David J Hunter, Mattias Johansson, Rudolf Kaaks, Laurence N Kolonel, Carmen Navarro, Elio Riboli, Carlotta Sacerdote, Meir Stampfer, Daniel O Stram, Michael J Thun, Dimitrios Trichopoulos, Jarmo Virtamo, Stephanie J Weinstein, Meredith Yeager, Brian Henderson, Jing Ma, Loic Le Marchand, Demetrius Albanes, and Peter Kraft
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade < 8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.
Published: 2011
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35. Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).

Author: Daniele Campa, Anika Hüsing, Angelika Stein, Lucie Dostal, Heiner Boeing, Tobias Pischon, Anne Tjønneland, Nina Roswall, Kim Overvad, Jane Nautrup Østergaard, Laudina Rodríguez, Núria Sala, Maria-José Sánchez, Nerea Larrañaga, José María Huerta, Aurelio Barricarte, Kay-Tee Khaw, Nicholas Wareham, Ruth C Travis, Naomi E Allen, Pagona Lagiou, Antonia Trichopoulou, Dimitrios Trichopoulos, Domenico Palli, Sabina Sieri, Rosario Tumino, Carlotta Sacerdote, Henk van Kranen, H Bas Bueno-de-Mesquita, Göran Hallmans, Mattias Johansson, Isabelle Romieu, Mazda Jenab, David G Cox, Afshan Siddiq, Elio Riboli, Federico Canzian, and Rudolf Kaaks
Subjects: Medicine, Science
Abstract: The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p
Published: 2011
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36. Association between TAS2R38 gene polymorphisms and colorectal cancer risk: a case-control study in two independent populations of Caucasian origin.

Author: Maura Carrai, Verena Steinke, Pavel Vodicka, Barbara Pardini, Nils Rahner, Elke Holinski-Feder, Monika Morak, Hans K Schackert, Heike Görgens, Susanne Stemmler, Beate Betz, Matthias Kloor, Christoph Engel, Reinhard Büttner, Alessio Naccarati, Ludmila Vodickova, Jan Novotny, Angelika Stein, Kari Hemminki, Peter Propping, Asta Försti, Federico Canzian, Roberto Barale, and Daniele Campa
Subjects: Medicine, Science
Abstract: Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99-1.67; P(value) = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06-1.75; P(value) = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12-1.61; P(value) = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin.
Published: 2011
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37. Pancreatic cancer susceptibility loci and their role in survival.

Author: Cosmeri Rizzato, Daniele Campa, Nathalia Giese, Jens Werner, P Sivaramakrishna Rachakonda, Rajiv Kumar, Michaela Schanné, William Greenhalf, Eithne Costello, Kay-Tee Khaw, Tim J Key, Afshan Siddiq, Justo Lorenzo-Bermejo, Barbara Burwinkel, John P Neoptolemos, Markus W Büchler, Jörg D Hoheisel, Andrea Bauer, and Federico Canzian
Subjects: Medicine, Science
Abstract: Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.
Published: 2011
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38. TAS2R38 polymorphisms, Helicobacter pylori infection and susceptibility to gastric cancer and premalignant gastric lesions

Author: Elena Kasamatsu, Federico Canzian, María Mercedes Bravo, Lourdes Flores-Luna, Nubia Muñoz, Cosmeri Rizzato, Jorge Vivas, Matteo Giaccherini, Antonella Lupetti, Daniele Campa, Ikuko Kato, and Manuel Gentiluomo
Subjects: Cancer Research, medicine.medical_specialty, Genotype, Epidemiology, premalignant gastric lesions, Gastroenterology, susceptibility, Helicobacter Infections, Receptors, G-Protein-Coupled, genetic polymorphisms, Stomach Neoplasms, Internal medicine, Medicine, CagA, Humans, Allele, biology, Helicobacter pylori, business.industry, gastric cancer, Haplotype, Public Health, Environmental and Occupational Health, Cancer, Odds ratio, biology.organism_classification, medicine.disease, Oncology, business, Precancerous Conditions, Cancer Etiology
Abstract: Background Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. Methods We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Results Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. Conclusion In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.
Published: 2023

39. A pleiotropic variant in <scp> DNAJB4 </scp> is associated with multiple myeloma risk

Author: Marco Dicanio, Matteo Giaccherini, Alyssa Clay‐Gilmour, Angelica Macauda, Juan Sainz, Mitchell J. Machiela, Malwina Rybicka‐Ramos, Aaron D. Norman, Agata Tyczyńska, Stephen J. Chanock, Torben Barington, Shaji K. Kumar, Parveen Bhatti, Wendy Cozen, Elizabeth E. Brown, Anna Suska, Eva K. Haastrup, Robert Z. Orlowski, Marek Dudziński, Ramon Garcia‐Sanz, Marcin Kruszewski, Joaquin Martinez‐Lopez, Katia Beider, Elżbieta Iskierka‐Jazdzewska, Matteo Pelosini, Sonja I. Berndt, Małgorzata Raźny, Krzysztof Jamroziak, S. Vincent Rajkumar, Artur Jurczyszyn, Annette Juul Vangsted, Pilar Garrido Collado, Ulla Vogel, Jonathan N. Hofmann, Mario Petrini, Aleksandra Butrym, Susan L. Slager, Elad Ziv, Edyta Subocz, Graham G. Giles, Niels Frost Andersen, Grzegorz Mazur, Marzena Watek, Fabienne Lesueur, Michelle A. T. Hildebrandt, Daria Zawirska, Lene Hyldahl Ebbesen, Herlander Marques, Federica Gemignani, Charles Dumontet, Judit Várkonyi, Gabriele Buda, Arnon Nagler, Agnieszka Druzd‐Sitek, Xifeng Wu, Katalin Kadar, Nicola J. Camp, Norbert Grzasko, Rosalie G. Waller, Celine Vachon, Federico Canzian, and Daniele Campa
Subjects: Cancer Research, genetic susceptibility, multiple myeloma, pleiotropy, pleiotropy scan, polymorphisms, Humans, Oncogenes, Alleles, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Predisposition to Disease, HSP40 Heat-Shock Proteins, DNA-Binding Proteins, RNA-Binding Proteins, Multiple Myeloma, Single Nucleotide, Oncology, Polymorphism
Abstract: 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.
Published: 2022

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

Author: Angelica Macauda, Alyssa Clay-Gilmour, Thomas Hielscher, Michelle A.T. Hildebrandt, Marcin Kruszewski, Robert Z. Orlowski, Shaji K. Kumar, Elad Ziv, Enrico Orciuolo, Elizabeth E. Brown, Asta Försti, Rosalie G. Waller, Mitchell J. Machiela, Stephen J. Chanock, Nicola J. Camp, Marcin Rymko, Małgorzata Raźny, Wendy Cozen, Judit Várkonyi, Chiara Piredda, Matteo Pelosini, Alem A. Belachew, Edyta Subocz, Kari Hemminki, Malwina Rybicka-Ramos, Graham G. Giles, Roger L. Milne, Jonathan N. Hofmann, Jan Maciej Zaucha, Annette Juul Vangsted, Hartmut Goldschmidt, S. Vincent Rajkumar, Waldemar Tomczak, Juan Sainz, Aleksandra Butrym, Marzena Watek, Elżbieta Iskierka-Jazdzewska, Gabriele Buda, Dennis P. Robinson, Artur Jurczyszyn, Marek Dudziński, Joaquin Martinez-Lopez, Jason P. Sinnwell, Susan L. Slager, Krzysztof Jamroziak, Rui Manuel Vieira Reis, Niels Weinhold, Parveen Bhatti, Luis G. Carvajal-Carmona, Daria Zawirska, Aaron D. Norman, Grzegorz Mazur, Sonja I. Berndt, Daniele Campa, Celine M. Vachon, and Federico Canzian
Subjects: Oncology, Risk Factors, Epidemiology, Humans, Genetic Predisposition to Disease, Multiple Myeloma, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: 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.
Published: 2022

41. A polymorphic variant in telomere maintenance is associated with worrisome features and high-risk stigmata development in IPMNs

Author: Matteo Giaccherini, Manuel Gentiluomo, Paolo Giorgio Arcidiacono, Massimo Falconi, Sabrina Gloria Giulia Testoni, Laura Apadula, Gaetano Lauri, Gregorio Di Franco, Lorenzo Maria Fatucchi, Maria Chiara Petrone, Chiara Corradi, Stefano Crippa, Luca Morelli, Gabriele Capurso, and Daniele Campa
Subjects: Pancreatic Neoplasms, Cancer Research, Pancreatic Intraductal Neoplasms, Humans, General Medicine, Telomere, Carcinoma, Pancreatic Ductal, Retrospective Studies
Abstract: Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47–6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.
Published: 2022

42. Supplementary Data from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author: Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci
Abstract: Supplemental figures 1 and 2. Supplemental tables 1-7.
Published: 2023

43. Supplementary Figure 1 from Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study

Author: Rudolf Kaaks, Federico Canzian, Magdalena Stepien, So Yeon Kong, Talita Duarte-Salles, Elisabete Weiderpass, Mie Jareid, Eiliv Lund, Weimin Ye, Malin Sund, Peter M. Nilsson, Petra H. Peeters, H.B. Bueno-de-Mesquita, Afshan Siddiq, Elio Riboli, Paolo Vineis, Salvatore Panico, Alessio Naccarati, Rosario Tumino, Valeria Pala, Domenico Palli, Ruth C. Travis, Nicholas Wareham, Kay-Tee Khaw, Miren Dorronsoro, Eva Ardanaz, José María Huerta, Esther Molina-Montes, Eric J. Duell, J. Ramón Quirós, Heiner Boeing, Dimitrios Trichopoulos, Nikos Yiannakouris, Antonia Trichopoulou, Verena A. Katzke, Alexandra Nieters, Gianluca Severi, Antoine Racine, Marie-Christine Boutron-Ruault, Immaculata De Vivo, Björn Mergarten, and Daniele Campa
Abstract: Supplementary Figure 1 - non-linear relation with 4 knots restricted cubic spline between LTL and pancreatic cancer risk.
Published: 2023

44. Supplementary Table 1 from Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study

Author: Rudolf Kaaks, Federico Canzian, Magdalena Stepien, So Yeon Kong, Talita Duarte-Salles, Elisabete Weiderpass, Mie Jareid, Eiliv Lund, Weimin Ye, Malin Sund, Peter M. Nilsson, Petra H. Peeters, H.B. Bueno-de-Mesquita, Afshan Siddiq, Elio Riboli, Paolo Vineis, Salvatore Panico, Alessio Naccarati, Rosario Tumino, Valeria Pala, Domenico Palli, Ruth C. Travis, Nicholas Wareham, Kay-Tee Khaw, Miren Dorronsoro, Eva Ardanaz, José María Huerta, Esther Molina-Montes, Eric J. Duell, J. Ramón Quirós, Heiner Boeing, Dimitrios Trichopoulos, Nikos Yiannakouris, Antonia Trichopoulou, Verena A. Katzke, Alexandra Nieters, Gianluca Severi, Antoine Racine, Marie-Christine Boutron-Ruault, Immaculata De Vivo, Björn Mergarten, and Daniele Campa
Abstract: Supplementary Table 1 - Associations between LTL and pancreatic cancer risk adjusted for smoking status C-peptide and HbA1c levels
Published: 2023

45. Supplementary Table 2 from Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study

Author: Rudolf Kaaks, Federico Canzian, Magdalena Stepien, So Yeon Kong, Talita Duarte-Salles, Elisabete Weiderpass, Mie Jareid, Eiliv Lund, Weimin Ye, Malin Sund, Peter M. Nilsson, Petra H. Peeters, H.B. Bueno-de-Mesquita, Afshan Siddiq, Elio Riboli, Paolo Vineis, Salvatore Panico, Alessio Naccarati, Rosario Tumino, Valeria Pala, Domenico Palli, Ruth C. Travis, Nicholas Wareham, Kay-Tee Khaw, Miren Dorronsoro, Eva Ardanaz, José María Huerta, Esther Molina-Montes, Eric J. Duell, J. Ramón Quirós, Heiner Boeing, Dimitrios Trichopoulos, Nikos Yiannakouris, Antonia Trichopoulou, Verena A. Katzke, Alexandra Nieters, Gianluca Severi, Antoine Racine, Marie-Christine Boutron-Ruault, Immaculata De Vivo, Björn Mergarten, and Daniele Campa
Abstract: Supplementary Table 2 - Associations between LTL and pancreatic cancer risk adjusted for Cpeptide and HbA1c levels considering only microscopically confirmed cases.
Published: 2023

46. Data from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author: Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci
Abstract: Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance:This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
Published: 2023

47. Supplementary table 8 from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author: Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci
Abstract: Supplemental Table 8. Enrichment in regulatory regions for rs842357 and related SNPs
Published: 2023

48. Genetic and non-genetic risk factors for early-onset pancreatic cancer

Author: Ylenia Nodari, Manuel Gentiluomo, Beatrice Mohelnikova-Duchonova, Edita Kreivenaite, Anna Caterina Milanetto, Jurgita Skieceviciene, Stefano Landi, Rita T Lawlor, Maria Chiara Petrone, Paolo Giorgio Arcidiacono, Martin Lovecek, Maria Gazouli, Maarten F. Bijlsma, Luca Morelli, Vytautas Kiudelis, Matteo Tacelli, Dalila Lucíola Zanette, Pavel Soucek, Faik Uzunoglu, Rudolf Kaaks, Jakob Izbicki, Ugo Boggi, Raffaele Pezzilli, Andrea Mambrini, Claudio Pasquali, Hanneke W. van Laarhoven, Verena Katzke, Giulia Martina Cavestro, Cosimo Sperti, Martin Loos, Anna Latiano, Bálint Erőss, Martin Oliverius, Theron Johnson, Daniela Basso, John P. Neoptolemos, Mateus Nóbrega Aoki, William Greenhalf, Pavel Vodicka, Livia Archibugi, Giuseppe Vanella, Maurizio Lucchesi, Renata Talar-Wojnarowska, Krzysztof Jamroziak, Mohammed Al Saeedi, Casper H.J. van Eijck, Juozas Kupcinskas, Tamás Hussein, Marta Puzzono, Stefania Bunduc, Mara Götz, Silvia Carrara, Andrea Szentesi, Francesca Tavano, Stefania Moz, Péter Hegyi, Claudio Luchini, Gabriele Capurso, Francesco Perri, Stefano Ermini, George Theodoropoulos, Giovanni Capretti, Orazio Palmieri, Laura Ginocchi, Niccolò Furbetta, Federico Canzian, Daniele Campa, Surgery, Internal medicine, Center of Experimental and Molecular Medicine, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Oncology, CCA - Cancer Treatment and Quality of Life, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Early onset, GWAS, Pancreatic cancer, Risk factor, Hepatology, SDG 3 - Good Health and Well-being, Gastroenterology, 03.02. Klinikai orvostan
Abstract: Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.
Published: 2023

49. Genetically Determined Telomere Length Is Associated with Pancreatic Neuroendocrine Neoplasms Onset

Author: Manuel Gentiluomo, Gabriele Capurso, Luca Morelli, Stefano Ermini, Claudio Pasquali, Anna Latiano, Francesca Tavano, William Greenhalf, Anna Caterina Milanetto, Stefano Landi, Susanne Roth, Ewa Malecka-Wojciesko, Eithne Costello, Krzysztof Jamroziak, Francesco Perri, Ugo Boggi, Daniela Basso, Fabio Farinati, Rudolf Kaaks, Giuseppe Vanella, Anna-Lea J. Gais Zurcher, Livia Archibugi, Rita T. Lawlor, Federico Canzian, and Daniele Campa
Subjects: Pancreatic Neoplasms, Cellular and Molecular Neuroscience, Endocrinology, Endocrine and Autonomic Systems, Case-Control Studies, Neoplasms, Endocrinology, Diabetes and Metabolism, Humans, Telomere, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Acid Anhydride Hydrolases
Abstract: Introduction: Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet. Methods: A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN. Results: An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33–2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G = 2.27, CI: 1.58–3.27, p = 8.80 × 10−6) and TERT-rs2736100 (ORC/A_vs_C/C = 2.03, CI: 1.42–2.91, p = 1.06 × 10−4). Conclusion: In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.
Published: 2022

50. The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years' experience of association studies to understand the genetic architecture of pancreatic cancer

Author: Daniele Campa, Manuel Gentiluomo, Angelika Stein, Mateus Nóbrega Aoki, Martin Oliverius, Ludmila Vodičková, Krzysztof Jamroziak, George Theodoropoulos, Claudio Pasquali, William Greenhalf, Paolo Giorgio Arcidiacono, Faik Uzunoglu, Raffaele Pezzilli, Claudio Luchini, Marta Puzzono, Martin Loos, Matteo Giaccherini, Verena Katzke, Andrea Mambrini, Edita Kiudeliene, Kauffmann Emanuele Federico, Julia Johansen, Tamás Hussein, Beatrice Mohelnikova-Duchonova, Casper H.J. van Eijck, Hermann Brenner, Riccardo Farinella, Juan Sainz Pérez, Martin Lovecek, Markus W. Büchler, Viktor Hlavac, Jakob R. Izbicki, Thilo Hackert, Roger Chammas, Alessandro Zerbi, Rita Lawlor, Alessio Felici, Mara Götz, Gabriele Capurso, Laura Ginocchi, Maria Gazouli, Juozas Kupcinskas, Giulia Martina Cavestro, Pavel Vodicka, Stefania Moz, John P. Neoptolemos, Lumir Kunovsky, Stig E. Bojesen, Silvia Carrara, Domenica Gioffreda, Egidijus Morkunas, Olga Abian, Stefania Bunduc, Daniela Basso, Ugo Boggi, Barbara Wlodarczyk, Andrea Szentesi, Giuseppe Vanella, Inna Chen, Maarten F. Bijlsma, Vytautas Kiudelis, Stefano Landi, Ben Schöttker, Chiara Corradi, Nathalia Giese, Rudolf Kaaks, Giulia Peduzzi, Péter Hegyi, Luca Morelli, Niccolò Furbetta, Pavel Soucek, Anna Latiano, Renata Talar-Wojnarowska, Sidsel C. Lindgaard, Frederike Dijk, Anna Caterina Milanetto, Francesca Tavano, Klara Cervena, Bálint Erőss, Sabrina G. Testoni, Judith H.E. Verhagen-Oldenampsen, Ewa Małecka-Wojciesko, Eithne Costello, Roberto Salvia, Evaristo Maiello, Stefano Ermini, Cosimo Sperti, Bernd Holleczek, Francesco Perri, Jurgita Skieceviciene, Livia Archibugi, Maurizio Lucchesi, Cosmeri Rizzato, and Federico Canzian
Subjects: chronic pancreatitis, Pancreatic cancer, Pancreatic ductal adenocarcinoma, Pancreatic neuroendocrine tumors, Intraductal papillary mucinous neoplasms, Chronic pancreatitis, Genetic epidemiology, Consortium, genetic epidemiology, pancreatic neuroendocrine tumors, SDG 3 - Good Health and Well-being, Oncology, pancreatic ductal adenocarcinoma, consortium, Hematology, intraductal papillary mucinous neoplasms
Abstract: Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.
Published: 2023

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