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1. Association of genetic variants affecting microRNAs and pancreatic cancer risk

Author

Lu, Y., Corradi, C., Gentiluomo, M., Theodoropoulos, G.E., Roth, S., Maiello, E., Morelli, L., L.Archibugi, Izbicki, J.R., Sarlós, P., Kiudelis, V., Oliverius, M., López de Maturana, E., Aoki, M.N., Vashist, Y., van Eijck, C.H.J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Souček, P., Neoptolemos, J., Di Franco, G., Sperti, C., Kauffmann, E.F., Hlaváč, V., Uzunoğlu, F.G., Ermini, S., Małecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelníková-Duchoňová, B., Bambi, F., Petrone, M.C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A.C., Ginocchi, L., Loveček, M., Puzzono, M., van Laarhoven, H.W.M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P.G., Izbéki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M.L., Costello-Goldring, E., Cavestro, G.M., Szentesi, A., Tavano, F., Włodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Schneider, M.A., Latiano, A., Gioffreda, D., Testoni, S.G.G., Malats, N., Kupcinskas, J., Lawlor, R.T., Capurso, G., Campa, D., and Canzian, F.

Published
2021
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2. Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Author

Sub ISEP overig, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Lu, Y., Corradi, C., Gentiluomo, M., López de Maturana, E., Theodoropoulos, G.E., Roth, S., Maiello, E., Morelli, L., Archibugi, L., Izbicki, J.R., Sarlós, P., Kiudelis, V., Oliverius, M., Aoki, M.N., Vashist, Y., van Eijck, C.H.J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Souček, P., Neoptolemos, J.P., Di Franco, G., Sperti, C., Kauffmann, E.F., Hlaváč, V., Uzunoğlu, F.G., Ermini, S., Małecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelníková-Duchoňová, B., Bambi, F., Petrone, M.C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A.C., Ginocchi, L., Loveček, M., Puzzono, M., van Laarhoven, H.W.M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P.G., Izbéki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M.L., Costello-Goldring, E., Cavestro, G.M., Szentesi, A., Tavano, F., Włodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Vermeulen, R.C.H., Schneider, M.A., Latiano, A., Gioffreda, D., Testoni, S.G.G., Kupcinskas, J., Lawlor, R.T., Capurso, G., Malats, N., Campa, D., Canzian, F., Sub ISEP overig, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Lu, Y., Corradi, C., Gentiluomo, M., López de Maturana, E., Theodoropoulos, G.E., Roth, S., Maiello, E., Morelli, L., Archibugi, L., Izbicki, J.R., Sarlós, P., Kiudelis, V., Oliverius, M., Aoki, M.N., Vashist, Y., van Eijck, C.H.J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Souček, P., Neoptolemos, J.P., Di Franco, G., Sperti, C., Kauffmann, E.F., Hlaváč, V., Uzunoğlu, F.G., Ermini, S., Małecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelníková-Duchoňová, B., Bambi, F., Petrone, M.C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A.C., Ginocchi, L., Loveček, M., Puzzono, M., van Laarhoven, H.W.M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P.G., Izbéki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M.L., Costello-Goldring, E., Cavestro, G.M., Szentesi, A., Tavano, F., Włodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Vermeulen, R.C.H., Schneider, M.A., Latiano, A., Gioffreda, D., Testoni, S.G.G., Kupcinskas, J., Lawlor, R.T., Capurso, G., Malats, N., Campa, D., and Canzian, F.

Published
2021

3. Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Author

Sub IER overig, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Lu, Y., Corradi, C., Gentiluomo, M., López de Maturana, E., Theodoropoulos, G.E., Roth, S., Maiello, E., Morelli, L., Archibugi, L., Izbicki, J.R., Sarlós, P., Kiudelis, V., Oliverius, M., Aoki, M.N., Vashist, Y., van Eijck, C.H.J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Souček, P., Neoptolemos, J.P., Di Franco, G., Sperti, C., Kauffmann, E.F., Hlaváč, V., Uzunoğlu, F.G., Ermini, S., Małecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelníková-Duchoňová, B., Bambi, F., Petrone, M.C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A.C., Ginocchi, L., Loveček, M., Puzzono, M., van Laarhoven, H.W.M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P.G., Izbéki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M.L., Costello-Goldring, E., Cavestro, G.M., Szentesi, A., Tavano, F., Włodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Vermeulen, R.C.H., Schneider, M.A., Latiano, A., Gioffreda, D., Testoni, S.G.G., Kupcinskas, J., Lawlor, R.T., Capurso, G., Malats, N., Campa, D., Canzian, F., Sub IER overig, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Lu, Y., Corradi, C., Gentiluomo, M., López de Maturana, E., Theodoropoulos, G.E., Roth, S., Maiello, E., Morelli, L., Archibugi, L., Izbicki, J.R., Sarlós, P., Kiudelis, V., Oliverius, M., Aoki, M.N., Vashist, Y., van Eijck, C.H.J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Souček, P., Neoptolemos, J.P., Di Franco, G., Sperti, C., Kauffmann, E.F., Hlaváč, V., Uzunoğlu, F.G., Ermini, S., Małecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelníková-Duchoňová, B., Bambi, F., Petrone, M.C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A.C., Ginocchi, L., Loveček, M., Puzzono, M., van Laarhoven, H.W.M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P.G., Izbéki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M.L., Costello-Goldring, E., Cavestro, G.M., Szentesi, A., Tavano, F., Włodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Vermeulen, R.C.H., Schneider, M.A., Latiano, A., Gioffreda, D., Testoni, S.G.G., Kupcinskas, J., Lawlor, R.T., Capurso, G., Malats, N., Campa, D., and Canzian, F.

Published
2021

7. Evaluation of UHRF1 and the antioxidant response pathway in pancreatic cancer and the prediction of response to treatment

Author

Gana, T., Costello-Goldring, E., Greenhalf, W., and Liloglou, T.

Subjects
616.99
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterised by very poor survival. The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic cancer, although its role in this cancer type is not fully understood. UHRF1 is a nuclear protein involved in epigenetic regulation. Our laboratory recently established that UHRF1 suppresses Keap1, an important negative regulator of the Nrf2 pathway. The aim of this study was to explore how UHRF1 contributes to Nrf2 function in pancreatic cancer cells and in pancreatic stellate cells, and to determine whether UHRF1 or NQO1, a downstream marker of Nrf2 activity could be predictive of PDAC treatment response. Depletion of UHRF1 from PDAC cells was associated with transcriptional upregulation of KEAP1, decreased levels of Nrf2 and Nrf2-regulated downstream proteins (NQO1 and AKR1C1), increased oxidative stress in the form of lower glutathione levels and increased reactive oxygen species. UHRF1 depletion enhanced cell cycle arrest, and concomitant depletion of UHRF1 and Keap1 reversed this effect, restored Nrf2 levels and reversed the increase in reactive oxygen species. The expression of UHRF1 in human pancreatic stellate cells (hPSCs) was limited to a small subset of cells. Analysis in Nrf2-null mouse pancreatic stellate cells was precluded by the fact that these cells, unlike their wild-type counterparts could not be maintained in culture. Histological analysis of the pancreata of Nrf2-null mice revealed early signs of pancreatitis. Germline single nucleotide polymorphisms (SNPs) were analysed in patients with advanced PDAC (n=140) from TeloVac and ViP clinical trials. The NQO1 rs1800566 CC homozygous major genotype was associated with poor survival (p=0.01) and the combined NQO1 rs1800566 and SRXN1 rs6053666 SNPs were prognostic of survival in these patients (p=0.039). No SNP–related differences in survival for NRF2 rs2886162 and SRXN1 rs6053666 variants were observed (p=0.405 and p=0.634 respectively). To determine whether UHRF1 or NQO1 expression are predictive of PDAC patient response to treatment, tissue microarrays from 349 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1) were analysed by immunohistochemistry for these proteins. Patients were dichotomized into low and high expression for nuclear UHRF1 and cytoplasmic NQO1 levels respectively and groups compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. UHRF1 was expressed in 181 of 199 (90.9%) PDAC tumours. Its levels were not associated with survival in the observation only group, or in either 5FU/folinic acid or gemcitabine treated groups (p=0.882, p=0.34 and p=0.92 respectively). Interestingly, an inverse relationship between UHRF1 and diabetes was apparent (p=0.005). NQO1 was expressed in the cytoplasm of 197 (95.2%) PDAC tumours. NQO1 levels were not associated with survival for the patents in the observation only group (p=0.301). However, median survival for patients treated with gemcitabine was 13.7 (95% CI 10.2 to 16.8) months for those with low NQO1 expression versus 24.2 (95% CI 16.3 to 29.5) months for those with high NQO1 expression (p=0.01). For the 5FU/folinic acid group, median survival was 13.4 (95% CI 10.9 to 19.6) and 21.8 (95 % CI 16.9 to 25.7) months for those with low and high NQO1 levels respectively (p=0.08). Multivariable Cox proportional hazard analysis in gemcitabine treated patients, revealed that NQO1 expression was not an independent predictive factor in gemcitabine-treated (p=0.19) patients. In summary, UHRF1 regulates Nrf2 in PDAC. UHRF1 levels are not prognostic, nor are they predictive of response to treatment in this disease. Interestingly, UHRF1 levels are inversely associated with diabetes, a finding that merits further study. By contrast, the NQO1 SNP rs1800566 is prognostic in advanced PDAC patients and NQO1 protein expression is not an independent predictive marker of response to adjuvant gemcitabine treatment in PDAC patients.

Published
2017
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8. 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, Federico Canzian, Sub IER overig, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Internal medicine, Surgery, Lu, Y., Corradi, C., Gentiluomo, M., Lopez de Maturana, E., Theodoropoulos, G. E., Roth, S., Maiello, E., Morelli, L., Archibugi, L., Izbicki, J. R., Sarlos, P., Kiudelis, V., Oliverius, M., Aoki, M. N., Vashist, Y., van Eijck, C. H. J., Gazouli, M., Talar-Wojnarowska, R., Mambrini, A., Pezzilli, R., Bueno-de-Mesquita, B., Hegyi, P., Soucek, P., Neoptolemos, J. P., Di Franco, G., Sperti, C., Kauffmann, E. F., Hlavac, V., Uzunoglu, F. G., Ermini, S., Malecka-Panas, E., Lucchesi, M., Vanella, G., Dijk, F., Mohelnikova-Duchonova, B., Bambi, F., Petrone, M. C., Jamroziak, K., Guo, F., Kolarova, K., Capretti, G., Milanetto, A. C., Ginocchi, L., Lovecek, M., Puzzono, M., van Laarhoven, H. W. M., Carrara, S., Ivanauskas, A., Papiris, K., Basso, D., Arcidiacono, P. G., Izbeki, F., Chammas, R., Vodicka, P., Hackert, T., Pasquali, C., Piredda, M. L., Costello-Goldring, E., Cavestro, G. M., Szentesi, A., Tavano, F., Wlodarczyk, B., Brenner, H., Kreivenaite, E., Gao, X., Bunduc, S., Vermeulen, R. C. H., Schneider, M. A., Latiano, A., Gioffreda, D., Testoni, S. G. G., Kupcinskas, J., Lawlor, R. T., Capurso, G., Malats, N., Campa, D., Canzian, F., Pathology, AII - Cancer immunology, CCA - Cancer biology and immunology, Oncology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Linkage disequilibrium, In silico, pancreatic cancer, pancreatic ductal adenocarcinoma, Single-nucleotide polymorphism, Biology, QH426-470, susceptibility, genetic polymorphisms, miRNA, SDG 3 - Good Health and Well-being, Pancreatic cancer, medicine, Genetics, SNP, Genetics(clinical), 03.02. Klinikai orvostan, Gene, Genotyping, Genetics (clinical), Original Research, Heritability, medicine.disease, Molecular Medicine
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

9. EVALUATION OF UHRF1 AND THE ANTIOXIDANT RESPONSE PATHWAY IN PANCREATIC CANCER AND THE PREDICTION OF RESPONSE TO TREATMENT

Author

Gana, T, Costello-Goldring, E, Greenhalf, W, and Liloglou, T

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterised by very poor survival. The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic cancer, although its role in this cancer type is not fully understood. UHRF1 is a nuclear protein involved in epigenetic regulation. Our laboratory recently established that UHRF1 suppresses Keap1, an important negative regulator of the Nrf2 pathway. The aim of this study was to explore how UHRF1 contributes to Nrf2 function in pancreatic cancer cells and in pancreatic stellate cells, and to determine whether UHRF1 or NQO1, a downstream marker of Nrf2 activity could be predictive of PDAC treatment response. Depletion of UHRF1 from PDAC cells was associated with transcriptional upregulation of KEAP1, decreased levels of Nrf2 and Nrf2-regulated downstream proteins (NQO1 and AKR1C1), increased oxidative stress in the form of lower glutathione levels and increased reactive oxygen species. UHRF1 depletion enhanced cell cycle arrest, and concomitant depletion of UHRF1 and Keap1 reversed this effect, restored Nrf2 levels and reversed the increase in reactive oxygen species. The expression of UHRF1 in human pancreatic stellate cells (hPSCs) was limited to a small subset of cells. Analysis in Nrf2-null mouse pancreatic stellate cells was precluded by the fact that these cells, unlike their wild-type counterparts could not be maintained in culture. Histological analysis of the pancreata of Nrf2-null mice revealed early signs of pancreatitis. Germline single nucleotide polymorphisms (SNPs) were analysed in patients with advanced PDAC (n=140) from TeloVac and ViP clinical trials. The NQO1 rs1800566 CC homozygous major genotype was associated with poor survival (p=0.01) and the combined NQO1 rs1800566 and SRXN1 rs6053666 SNPs were prognostic of survival in these patients (p=0.039). No SNP–related differences in survival for NRF2 rs2886162 and SRXN1 rs6053666 variants were observed (p=0.405 and p=0.634 respectively). To determine whether UHRF1 or NQO1 expression are predictive of PDAC patient response to treatment, tissue microarrays from 349 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1) were analysed by immunohistochemistry for these proteins. Patients were dichotomized into low and high expression for nuclear UHRF1 and cytoplasmic NQO1 levels respectively and groups compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. UHRF1 was expressed in 181 of 199 (90.9%) PDAC tumours. Its levels were not associated with survival in the observation only group, or in either 5FU/folinic acid or gemcitabine treated groups (p=0.882, p=0.34 and p=0.92 respectively). Interestingly, an inverse relationship between UHRF1 and diabetes was apparent (p=0.005). NQO1 was expressed in the cytoplasm of 197 (95.2%) PDAC tumours. NQO1 levels were not associated with survival for the patents in the observation only group (p=0.301). However, median survival for patients treated with gemcitabine was 13.7 (95% CI 10.2 to 16.8) months for those with low NQO1 expression versus 24.2 (95% CI 16.3 to 29.5) months for those with high NQO1 expression (p=0.01). For the 5FU/folinic acid group, median survival was 13.4 (95% CI 10.9 to 19.6) and 21.8 (95 % CI 16.9 to 25.7) months for those with low and high NQO1 levels respectively (p=0.08). Multivariable Cox proportional hazard analysis in gemcitabine treated patients, revealed that NQO1 expression was not an independent predictive factor in gemcitabine-treated (p=0.19) patients. In summary, UHRF1 regulates Nrf2 in PDAC. UHRF1 levels are not prognostic, nor are they predictive of response to treatment in this disease. Interestingly, UHRF1 levels are inversely associated with diabetes, a finding that merits further study. By contrast, the NQO1 SNP rs1800566 is prognostic in advanced PDAC patients and NQO1 protein expression is not an independent predictive marker of response to adjuvant gemcitabine treatment in PDAC patients.

10. Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

Author

Quinn LM, Haldenby S, Antzcak P, Fowler A, Bullock K, Kenny J, Gilbert T, Andrews T, Diaz-Nieto R, Fenwick S, Jones R, Costello-Goldring E, Poston G, Greenhalf W, Palmer D, Malik H, and Goldring C

Subjects
Humans, Bile Ducts, Intrahepatic pathology, Mutation, Genomics, DNA Mutational Analysis, MAP Kinase Kinase Kinases genetics, Klatskin Tumor pathology, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology
Abstract

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype., (© 2023. The Author(s).)

Published
2023
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11. Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk.

Author

Lu Y, Corradi C, Gentiluomo M, López de Maturana E, Theodoropoulos GE, Roth S, Maiello E, Morelli L, Archibugi L, Izbicki JR, Sarlós P, Kiudelis V, Oliverius M, Aoki MN, Vashist Y, van Eijck CHJ, Gazouli M, Talar-Wojnarowska R, Mambrini A, Pezzilli R, Bueno-de-Mesquita B, Hegyi P, Souček P, Neoptolemos JP, Di Franco G, Sperti C, Kauffmann EF, Hlaváč V, Uzunoğlu FG, Ermini S, Małecka-Panas E, Lucchesi M, Vanella G, Dijk F, Mohelníková-Duchoňová B, Bambi F, Petrone MC, Jamroziak K, Guo F, Kolarova K, Capretti G, Milanetto AC, Ginocchi L, Loveček M, Puzzono M, van Laarhoven HWM, Carrara S, Ivanauskas A, Papiris K, Basso D, Arcidiacono PG, Izbéki F, Chammas R, Vodicka P, Hackert T, Pasquali C, Piredda ML, Costello-Goldring E, Cavestro GM, Szentesi A, Tavano F, Włodarczyk B, Brenner H, Kreivenaite E, Gao X, Bunduc S, Vermeulen RCH, Schneider MA, Latiano A, Gioffreda D, Testoni SGG, Kupcinskas J, Lawlor RT, Capurso G, Malats N, Campa D, and Canzian F

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Corradi, Gentiluomo, López de Maturana, Theodoropoulos, Roth, Maiello, Morelli, Archibugi, Izbicki, Sarlós, Kiudelis, Oliverius, Aoki, Vashist, van Eijck, Gazouli, Talar-Wojnarowska, Mambrini, Pezzilli, Bueno-de-Mesquita, Hegyi, Souček, Neoptolemos, Di Franco, Sperti, Kauffmann, Hlaváč, Uzunoğlu, Ermini, Małecka-Panas, Lucchesi, Vanella, Dijk, Mohelníková-Duchoňová, Bambi, Petrone, Jamroziak, Guo, Kolarova, Capretti, Milanetto, Ginocchi, Loveček, Puzzono, van Laarhoven, Carrara, Ivanauskas, Papiris, Basso, Arcidiacono, Izbéki, Chammas, Vodicka, Hackert, Pasquali, Piredda, Costello-Goldring, Cavestro, Szentesi, Tavano, Włodarczyk, Brenner, Kreivenaite, Gao, Bunduc, Vermeulen, Schneider, Latiano, Gioffreda, Testoni, Kupcinskas, Lawlor, Capurso, Malats, Campa and Canzian.)

Published
2021
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