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98 results on '"Gioffreda, D."'

1. A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma

Author

Giaccherini, M, primary, Rende, M, additional, Gentiluomo, M, additional, Corradi, C, additional, Archibugi, L, additional, Ermini, S, additional, Maiello, E, additional, Morelli, L, additional, van Eijck, C H J, additional, Cavestro, G M, additional, Schneider, M, additional, Mickevicius, A, additional, Adamonis, K, additional, Basso, D, additional, Hlavac, V, additional, Gioffreda, D, additional, Talar-Wojnarowska, R, additional, Schöttker, B, additional, Lovecek, M, additional, Vanella, G, additional, Gazouli, M, additional, Uno, M, additional, Malecka-Wojciesko, E, additional, Vodicka, P, additional, Goetz, M, additional, Bijlsma, M F, additional, Petrone, M C, additional, Bazzocchi, F, additional, Kiudelis, M, additional, Szentesi, A, additional, Carrara, S, additional, Nappo, G, additional, Brenner, H, additional, Milanetto, A C, additional, Soucek, P, additional, Katzke, V, additional, Peduzzi, G, additional, Rizzato, C, additional, Pasquali, C, additional, Chen, X, additional, Capurso, G, additional, Hackert, T, additional, Bueno-de-Mesquita, B, additional, Uzunoglu, F G G, additional, Hegyi, P, additional, Greenhalf, W, additional, Theodoropoulos, G E E, additional, Sperti, C, additional, Perri, F, additional, Oliverius, M, additional, Mambrini, A, additional, Tavano, F, additional, Farinella, R, additional, Arcidiacono, P G, additional, Lucchesi, M, additional, Bunduc, S, additional, Kupcinskas, J, additional, Di Franco, G, additional, Stocker, S, additional, Neoptolemos, J P, additional, Bambi, F, additional, Jamroziak, K, additional, Testoni, S G G, additional, Aoki, M N, additional, Mohelnikova-Duchonova, B, additional, Izbicki, J R, additional, Pezzilli, R, additional, Lawlor, R T, additional, Kauffmann, E F, additional, López de Maturana, E, additional, Malats, N, additional, Canzian, F, additional, and Campa, D, additional

Published
2024
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2. 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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3. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Author

Corradi, C. Gentiluomo, M. Gajdán, L. Cavestro, G.M. Kreivenaite, E. Di Franco, G. Sperti, C. Giaccherini, M. Petrone, M.C. Tavano, F. Gioffreda, D. Morelli, L. Soucek, P. Andriulli, A. Izbicki, J.R. Napoli, N. Małecka-Panas, E. Hegyi, P. Neoptolemos, J.P. Landi, S. Vashist, Y. Pasquali, C. Lu, Y. Cervena, K. Theodoropoulos, G.E. Moz, S. Capurso, G. Strobel, O. Carrara, S. Hackert, T. Hlavac, V. Archibugi, L. Oliverius, M. Vanella, G. Vodicka, P. Arcidiacono, P.G. Pezzilli, R. Milanetto, A.C. Lawlor, R.T. Ivanauskas, A. Szentesi, A. Kupcinskas, J. Testoni, S.G.G. Lovecek, M. Nentwich, M. Gazouli, M. Luchini, C. Zuppardo, R.A. Darvasi, E. Brenner, H. Gheorghe, C. Jamroziak, K. Canzian, F. Campa, D.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10−9). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism. © 2021 UICC

Published
2021

4. 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

5. 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

6. Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Author

Campa, D, Matarazzi, M, Greenhalf, W, Bijlsma, M, Saum, K-U, Pasquali, C, Van Laarhoven, H, Szentesi, A, Federici, F, Vodicka, P, Funel, N, Pezzilli, R, Bueno-De-Mesquita, HB, Vodickova, L, Basso, D, Obazee, O, Hackert, T, Soucek, P, Cuk, K, Kaiser, J, Sperti, C, Lovecek, M, Capurso, G, Mohelnikova-Duchonova, B, Khaw, K-T, König, A-K, Kupcinskas, J, Kaaks, R, Bambi, F, Archibugi, L, Mambrini, A, Cavestro, GM, Landi, S, Hegyi, P, Izbicki, JR, Gioffreda, D, Zambon, CF, Tavano, F, Talar-Wojnarowska, R, Jamroziak, K, Key, TJ, Fave, GD, Strobel, O, Jonaitis, L, Andriulli, A, Lawlor, RT, Pirozzi, F, Katzke, V, Valsuani, C, Vashist, YK, Brenner, H, Canzian, F, Campa, D., Matarazzi, M., Greenhalf, W., Bijlsma, M., Saum, K. -U., Pasquali, C., van Laarhoven, H., Szentesi, A., Federici, F., Vodicka, P., Funel, N., Pezzilli, R., Bueno-de-Mesquita, H. B., Vodickova, L., Basso, D., Obazee, O., Hackert, T., Soucek, P., Cuk, K., Kaiser, J., Sperti, C., Lovecek, M., Capurso, G., Mohelnikova-Duchonova, B., Khaw, K. -T., Konig, A. -K., Kupcinskas, J., Kaaks, R., Bambi, F., Archibugi, L., Mambrini, A., Cavestro, G. M., Landi, S., Hegyi, P., Izbicki, J. R., Gioffreda, D., Zambon, C. F., Tavano, F., Talar-Wojnarowska, R., Jamroziak, K., Key, T. J., Fave, G. D., Strobel, O., Jonaitis, L., Andriulli, A., Lawlor, R. T., Pirozzi, F., Katzke, V., Valsuani, C., Vashist, Y. K., Brenner, H., Canzian, F., Center of Experimental and Molecular Medicine, CCA - Cancer biology and immunology, Radiotherapy, Oncology, and AGEM - Re-generation and cancer of the digestive system

Subjects
Male, Cancer Research, pancreatic ductal adenocarcinoma, Polymorphism, Single Nucleotide, lymphocyte telomere length, genetic polymorphisms, association, Mendelian randomization, Oncology, Humans, genetic polymorphism, Lymphocytes, Telomerase, Telomere Shortening, Aged, Pancreatic Neoplasm, Ribonucleoprotein, Middle Aged, Telomere, Pancreatic Neoplasms, Europe, Ribonucleoproteins, Case-Control Studies, Female, Lymphocyte, Case-Control Studie, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, Human
Abstract

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10 −10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10 −6 , p trend = 3.27 × 10 −7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10 −9 for highest vs. lowest quintile; p = 1.82 × 10 −10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Published
2019

7. Associations between pancreatic expression quantitative trait loci (eQTLs) and pancreatic ductal adenocarcinoma risk

Author

Gentiluomo, M., Pistoni, L., Peduzzi, G., Lu, Y., Macauda, A., Hlavac, V., Vanella, G., Darvasi, E., Milanetto, A. C., Oliverius, M., Vashist, Y., Di Leo, M., Mohelnikova-Duchonova, B., Talar-Wojnarowska, R., Gheorghe, C., Petrone, M., Strobel, O., Arcidiacono, P., Vodickova, L., Szentesi, A., Capurso, G., Gajdan, L., Malleo, G., Theodoropoulos, G., Basso, D., Soucek, P., Brenner, H., Lawlor, R., Morelli, L., Ivanauskas, A., Kauffmann, E., Gazouli, M. Archibugi L., Nentwich, M., Lovecek, M., Cavestro, G., Vodicka, P., Landi, S., Tavano, F., Sperti, C., Hackert, T., Kupcinsckas, J., Pezzilli, R., Andriulli, A., Pollina, L., Kreivenaite, E., Gioffreda, D., Jamroziak, K., Hegyi, P., Izbicki, J., Testoni, S., Zuppardo, R., Bozzato, D., Neoptolemos, J., Canzian, F., and Campa, D

Published
2020

8. Polymorphic variants with non-coding RNA and risk of pancreatic ductal adenocarcinoma

Author

Gentiluomo, M., Corradi, C., Lu, Y., Giaccherini, M., Hegyi, P., Pezzilli, R., Tavano, F., Szentesi, A., Gajdan, L., Nentwich, M., Strobel, O., Gazouli, M., Cavestro, G., Darvasi, E., Arcidiacono, P., Landi, S., Luchini, C., Gioffreda, D., Kupcinsckas, J., Hackert, T., Neoptolemos, J., Morelli, L., Kreivenaite, E., Zuppardo, R., Carrara, S., Di Franco, G., Brenner, H., Hlavac, V., Sperti, C., Milanetto, A. C., Moz, S., Mohelnikova-Duchonova, B., Petrone, M., Lawlor, R., Vanella, G., Vashist, Y., Soucek, P., Vodicka, P., Cervena, K., Capurso, G., Malenka-Panas, E., Pasquali, C., Archibugi, L., Gheorghe, C., Andriulli, A., Ivanauskas, A., Theodoropoulos, G., Jamroziak, K., Izbicki, J., Testoni, S., Oliverius, M., Napoli, N., Canzian, F., and Campa, D.

Published
2020

9. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Campa, D. Gentiluomo, M. Obazee, O. Ballerini, A. Vodickova, L. Hegyi, P. Soucek, P. Brenner, H. Milanetto, A.C. Landi, S. Gao, X. Bozzato, D. Capurso, G. Tavano, F. Vashist, Y. Hackert, T. Bambi, F. Bursi, S. Oliverius, M. Gioffreda, D. Schöttker, B. Ivanauskas, A. Mohelnikova-Duchonova, B. Darvasi, E. Pezzilli, R. Małecka-Panas, E. Strobel, O. Gazouli, M. Katzke, V. Szentesi, A. Cavestro, G.M. Farkas, G., Jr. Izbicki, J.R. Moz, S. Archibugi, L. Hlavac, V. Vincze, Á. Talar-Wojnarowska, R. Rusev, B. Kupcinskas, J. Greenhalf, B. Dijk, F. Giese, N. Boggi, U. Andriulli, A. Busch, O.R. Vanella, G. Vodicka, P. Nentwich, M. Lawlor, R.T. Theodoropoulos, G.E. Jamroziak, K. Zuppardo, R.A. Moletta, L. Ginocchi, L. Kaaks, R. Neoptolemos, J.P. Lucchesi, M. Canzian, F.

Abstract

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10−4). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10−4). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. © 2020 UICC

Published
2020

13. A multifactorial score for pancreatic ductal adenocarcinoma risk prediction

Author

Gentiluomo, M., Galeotti, A. A., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwick, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Shroeder, C., Shottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlisma, M. F., Palmieri, G., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova – Duchonova, B., Hackert, T., Vahist, Y., Strouhal, O., van Laarhoven, C., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malencka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Bukler, M. W., Vodicka, P., Paiella, S, Canzian, F., and Campa, D. :.

Published
2019

14. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Gentiluomo, M., Obazee, O., Ballerini, A., Vodickova, L., Hegyi, P., Soucek, P., Brenner, H., Milanetto, A. C., Landi, S., Gao, X., Bozzato, D., Capurso, G., Tavano, F., Vashist, Y., Hackert, T., Bambi, F., Bursi, S., Oliverius, M., Gioffreda, D., Schöttker, B., Ivanauskas, A., Mohelnikova-Duchonova, B., Darvasi, E., Pezzilli, R., Małecka-Panas, E., Strobel, O., Gazouli, M., Katzke, V., Szentesi, A., Cavestro, G. M., Farkas, G. Jr., Izbicki, J. R., Moz, S., Archibugi, L., Hlavac, V., Vincze, A., Talar-Wojnarowska, R., Borislav, R., Kupcinskas, J., Greenhalf, B., Dijk, F., Giese, N., Boggi, U., Andriulli, A., Busch, O. R., Vanella, G., Vodicka, P., Nentwich, M., Lawlor, R. T., Theodoropoulos, G. E., Jamroziak, K., Zuppardo, R. A., Moletta, L., Ginocchi, L., Kaaks, R., Neoptolemos, J. P., Lucchesi, M., Canzian, F., and Campa, D.

Published
2019

16. SLC22A3 polymorphisms may influence overall patient survival-PANDORA study

Author

Mohelnikova-Duchonova, B, Strouhal, O, Hughes, Dj, Lovecek, M, Holcatova, I, Oliverius, M, Kala, Z, Campa, D, Rizzato, C, Canzian, F, Pezzilli, R, Talar-Wojnarowska, R, Malecka-Panas, E, Sperti, C, Zambon, Cf, Pedrazzoli, S, Fogar, P, Milanetto, A. C., Capurso, G, Delle Fave, G, Valente, R, Gazouli, M, Malleo, G, Lawlor, Rt, Strobel, O, Hackert, T, Giese, N, Vodicka, P, Vodickova, L, Landi, S, Tavano, F, Gioffreda, D, Piepoli, A, Pazienza, V, Mambrini, A, Bursi, S, Pacetti, P, Bambi, F, Ermini, S, Funel, N, and Soucek, P

Published
2018

17. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author

Campa, D. Pastore, M. Capurso, G. Hackert, T. Di Leo, M. Izbicki, J.R. Khaw, K.-T. Gioffreda, D. Kupcinskas, J. Pasquali, C. Macinga, P. Kaaks, R. Stigliano, S. Peeters, P.H. Key, T.J. Talar-Wojnarowska, R. Vodicka, P. Valente, R. Vashist, Y.K. Salvia, R. Papaconstantinou, I. Shimizu, Y. Valsuani, C. Zambon, C.F. Gazouli, M. Valantiene, I. Niesen, W. Mohelnikova-Duchonova, B. Hara, K. Soucek, P. Malecka-Panas, E. Bueno-de-Mesquita, H.B. Johnson, T. Brenner, H. Tavano, F. Fogar, P. Ito, H. Sperti, C. Butterbach, K. Latiano, A. Andriulli, A. Cavestro, G.M. Busch, O.R.C. Dijk, F. Greenhalf, W. Matsuo, K. Lombardo, C. Strobel, O. König, A.-K. Cuk, K. Strothmann, H. Katzke, V. Cantore, M. Mambrini, A. Oliverius, M. Pezzilli, R. Landi, S. Canzian, F.

Subjects
endocrine system diseases, digestive system diseases
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02–1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39–0.67, p = 1.10 × 10−6) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55–2.77, ptrend = 0.7 × 10−11). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. © 2017 UICC

Published
2018

18. Identification of recessively inherited genetic variants for pancreatic cancer risk

Author

Lu, Y., Gentiluomo, M., Macauda, A., Gioffreda, D., Gazouli, M., Petrone, M.C., Kelemen, D., L.Ginocchi, Morelli, L., Papiris, K., Greenhalf, W., Izbicki, J.R., Kiudelis, V., Mohelníková-Duchoňová, B., Bueno-de-Mesquita, B., Vodicka, P., Brenner, H., Diener, M.K., Pezzilli, R., Ivanauskas, A., Salvia, R., Szentesi, A., Aoki, M.N., Németh, B.C., Sperti, C., Jamroziak, K., Chammas, R., Oliverius, M., Archibugi, L., Ermini, S., Novák, J., Kupcinskas, J., Strouhal, O., Souček, P., Cavestro, G.M., Milanetto, A.C., Vanella, G., Neoptolemos, J.P., Theodoropoulos, G.E., van Laarhoven, H.W.M., Mambrini, A., Moz, S., Kala, Z., Loveček, M., Basso, D., Uzunoglu, F.G., Hackert, T., Testoni, S.G.G., Hlavac, V., Andriulli, A., Lucchesi, M., Tavano, F., Carrara, S., Hegyi, P., Arcidiacono, P.G., Busch, O.R., Lawlor, R.T., Puzzono, M., Boggi, U., Guo, F., Małecka-Panas, E., Capurso, G., Landi, S., R.Talar-Wojnarowska, Strobel, O., Gao, X., Vashist, Y., Campa, D., and Canzian, F.

Published
2021
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19. Association of variants of genes involved in mitochondrial metabolism with pancreatic cancer risk

Author

Peduzzi, G., Gentiluomo, M., Tavano, F., Arcidiacono, P.G., Ermini, S., Boggi, U., Cavestro, G.M., Capurso, G., Morelli, L., Milanetto, A.C., Pezzilli, R., Lawlor, R.T., Carrara, S., Lovecek, M., Souček, P., Vodičková, Guo, F., Hackert, T., Uzunoğlu, F.G., Gazouli, M., Párniczky, A., Kupcinskas, J., Bijlsm, M.F., Bueno-de-Mesquita, B., Vermeulen, R.C.H., van Eijck, C.H.J., Jamroziak, K., Talar-Wojnarowska, R., Greenhalf, W., Gioffreda, D., Petrone, M.C., Landi, S., Archibugi, L., Puzzono, M., Funel, N., Sperti, C., Piredda, M.L., Mohelnikova-Duchonova, B., Hlaváč, V., Gao, X., Schneider, M., Izbicki, J.R., Theodoropoulos, G., Bunduc, S., Kreivenaite, E., Busch, O.R., Małecka-Panas, E., Costello, E., Perri, F., Testoni, S.G.G., Vanella, G., Pasquali, C., Oliverius, M., H.Brenner, Loos, M., Götz, M., Georgiou, K., Erőss, B., Maiello, E., Szentes i, A., Bazzocchi, F., Basso, D., Neoptolemos, J.P., Hegyi, P., Kiudelis, V., Canzian, F., and Campa, D.

Published
2021
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20. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author

Campa, D, Pastore, M, Capurso, G, Hackert, T, Di Leo, M, Izbicki, JR, Khaw, K-T, Gioffreda, D, Kupcinskas, J, Pasquali, C, Macinga, P, Kaaks, R, Stigliano, S, Peeters, PH, Key, TJ, Talar-Wojnarowska, R, Vodicka, P, Valente, R, Vashist, YK, Salvia, R, Papaconstantinou, I, Shimizu, Y, Valsuani, C, Zambon, CF, Gazouli, M, Valantiene, I, Niesen, W, Mohelnikova-Duchonova, B, Hara, K, Soucek, P, Malecka-Panas, E, Bueno-de-Mesquita, HBA, Johnson, T, Brenner, H, Tavano, F, Fogar, P, Ito, H, Sperti, C, Butterbach, K, Latiano, A, Andriulli, A, Cavestro, GM, Busch, ORC, Dijk, F, Greenhalf, W, Matsuo, K, Lombardo, C, Strobel, O, König, A-K, Cuk, K, Strothmann, H, Katzke, V, Cantore, M, Mambrini, A, Oliverius, M, Pezzilli, R, Landi, S, Canzian, F, Other departments, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, Daniele, Pastore, Manuela, Capurso, Gabriele, Hackert, Thilo, Di Leo, Milena, Izbicki, Jakob R, Khaw, Kay tee, Gioffreda, Domenica, Kupcinskas, Juoza, Pasquali, Claudio, Macinga, Peter, Kaaks, Rudolf, Stigliano, Serena, Peeters, Petra H, Key, Timothy J, Talar wojnarowska, Renata, Vodicka, Pavel, Valente, Roberto, Vashist, Yogesh K, Salvia, Roberto, Papaconstantinou, Ioanni, Shimizu, Yasuhiro, Valsuani, Chiara, Zambon, Carlo Federico, Gazouli, Maria, Valantiene, Irena, Niesen, Willem, Mohelnikova duchonova, Beatrice, Hara, Kazuo, Soucek, Pavel, Malecka panas, Ewa, Bueno de mesquita, H. Ba, Johnson, Theron, Brenner, Herman, Tavano, Francesca, Fogar, Paola, Ito, Hidemi, Sperti, Cosimo, Butterbach, Katja, Latiano, Anna, Andriulli, Angelo, Cavestro, GIULIA MARTINA, Busch, Olivier R. C, Dijk, Frederike, Greenhalf, William, Matsuo, Keitaro, Lombardo, Carlo, Strobel, Oliver, König, Anna katharina, Cuk, Katarina, Strothmann, Hendrik, Katzke, Verena, Cantore, Maurizio, Mambrini, Andrea, Oliverius, Martin, Pezzilli, Raffaele, Landi, Stefano, and Canzian, Federico

Subjects
Adult, Male, Cancer Research, endocrine system diseases, Chronic pancreatiti, pancreatic ductal adenocarcinoma, Adenocarcinoma, Polymorphism, Single Nucleotide, genetic polymorphisms, Risk Factors, Pancreatitis, Chronic, Biomarkers, Tumor, genetic polymorphism, Humans, Trypsin, Chronic, Polymorphism, Aged, Retrospective Studies, Tumor, Carcinoma, association, Nuclear Proteins, Single Nucleotide, Middle Aged, ACUTE PANCREATITIS, Prognosis, digestive system diseases, PANCREATIC CANCER, Pancreatic Neoplasms, Pancreatitis, Oncology, Pancreatic Ductal, Case-Control Studies, Chronic pancreatitis, Carcinoma, Pancreatic Ductal, Female, Follow-Up Studies, Trypsinogen, Biomarkers
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639 rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous =1.19, 95% CI 1.02-1.38, p=0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous =0.51, 95% CI 0.39-0.67, p=1.10x10(-6) ) and MORC4-rs 12837024 (ORhomozygous =2.07 (1.55-2.77, ptrend =0.7x10(-11) ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639 rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. This article is protected by copyright. All rights reserved.

Published
2017

21. SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Author

Mohelnikova-Duchonova, B. Strouhal, O. Hughes, D.J. Holcatova, I. Oliverius, M. Kala, Z. Campa, D. Rizzato, C. Canzian, F. Pezzilli, R. Talar-Wojnarowska, R. Malecka-Panas, E. Sperti, C. Federico Zambon, C. Pedrazzoli, S. Fogar, P. Milanetto, A.C. Capurso, G. Delle Fave, G. Valente, R. Gazouli, M. Malleo, G. Teresa Lawlor, R. Strobel, O. Hackert, T. Giese, N. Vodicka, P. Vodickova, L. Landi, S. Tavano, F. Gioffreda, D. Piepoli, A. Pazienza, V. Mambrini, A. Pedata, M. Cantore, M. Bambi, F. Ermini, S. Funel, N. Lemstrova, R. Soucek, P.

Abstract

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted. © 2017 The Author(s).

Published
2017

22. Functional single nucleotide polymorphisms within the cyclindependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

Author

Campa, D. Pastore, M. Gentiluomo, M. Talar-Wojnarowska, R. Kupcinskas, J. Malecka-Panas, E. Neoptolemos, J.P. Niesen, W. Vodicka, P. Delle Fave, G. Bas Bueno-de-Mesquita, H. Gazouli, M. Pacetti, P. Di Leo, M. Ito, H. Klüter, H. Soucek, P. Corbo, V. Yamao, K. Hosono, S. Kaaks, R. Vashist, Y. Gioffreda, D. Strobel, O. Shimizu, Y. Dijk, F. Andriulli, A. Ivanauskas, A. Bugert, P. Tavano, F. Vodickova, L. Zambon, C.F. Lovecek, M. Landi, S. Key, T.J. Boggi, U. Pezzilli, R. Jamroziak, K. Mohelnikova-Duchonova, B. Mambrini, A. Bambi, F. Busch, O. Pazienza, V. Valente, R. Theodoropoulos, G.E. Hackert, T. Capurso, G. Cavestro, G.M. Pasquali, C. Basso, D. Sperti, C. Matsuo, K. Büchler, M. Khaw, K.-T. Izbicki, J. Costello, E. Katzke, V. Michalski, C. Stepien, A. Rizzato, C. Canzian, F.

Abstract

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.

Published
2016

23. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Author

Campa, D. Rizzato, C. Stolzenberg-Solomon, R. Pacetti, P. Vodicka, P. Cleary, S.P. Capurso, G. Bueno-De-Mesquita, H.B. Werner, J. Gazouli, M. Butterbach, K. Ivanauskas, A. Giese, N. Petersen, G.M. Fogar, P. Wang, Z. Bassi, C. Ryska, M. Theodoropoulos, G.E. Kooperberg, C. Li, D. Greenhalf, W. Pasquali, C. Hackert, T. Fuchs, C.S. Mohelnikova-Duchonova, B. Sperti, C. Funel, N. Dieffenbach, A.K. Wareham, N.J. Buring, J. Holcátová, I. Costello, E. Zambon, C.-F. Kupcinskas, J. Risch, H.A. Kraft, P. Bracci, P.M. Pezzilli, R. Olson, S.H. Sesso, H.D. Hartge, P. Strobel, O. Małecka-Panas, E. Visvanathan, K. Arslan, A.A. Pedrazzoli, S. Souček, P. Gioffreda, D. Key, T.J. Talar-Wojnarowska, R. Scarpa, A. Mambrini, A. Jacobs, E.J. Jamroziak, K. Klein, A. Tavano, F. Bambi, F. Landi, S. Austin, M.A. Vodickova, L. Brenner, H. Chanock, S.J. Delle Fave, G. Piepoli, A. Cantore, M. Zheng, W. Wolpin, B.M. Amundadottir, L.T. Canzian, F.

Abstract

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools. © 2015 UICC.

Published
2015

28. 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

29. Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

Author

John P. Neoptolemos, Krzysztof Jamroziak, Manuel Gentiluomo, Edita Kreivenaite, Oliver Strobel, Martin Lovecek, Núria Malats, Rita T. Lawlor, Angelica Macauda, Yogesh K. Vashist, Sabrina Gloria Giulia Testoni, Paolo Giorgio Arcidiacono, Raffaele Pezzilli, Gabriele Capurso, George Theodoropoulos, Andrea Szentesi, Giuseppe Vanella, Michael F. Nentwich, Pavel Vodicka, Luca Morelli, Audrius Ivanauskas, Angelo Andriulli, Giulia Martina Cavestro, Emanuele Federico Kauffmann, Renata Talar-Wojnarowska, Raffaella Alessia Zuppardo, Pavel Soucek, Viktor Hlavac, Daniele Campa, Laura Pistoni, PanGenEU Study Investigators, Evangelina López de Maturana, Milena Di Leo, Livia Archibugi, Maria Gazouli, Federico Canzian, Péter Hegyi, Cosimo Sperti, Anna Caterina Milanetto, László Gajdán, Domenica Gioffreda, Martin Oliverius, Beatrice Mohelnikova-Duchonova, Dania Bozzato, Maria Chiara Petrone, Stefano Landi, Thilo Hackert, Luca Pollina, Hermann Brenner, Ye Lu, Cristian Gheorghe, Daniela Basso, Giuseppe Malleo, Erika Darvasi, Ludmila Vodickova, Juozas Kupcinskas, Jakob R. Izbicki, Francesca Tavano, Pistoni, L., Gentiluomo, M., Lu, Y., de Maturana, E. L., Hlavac, V., Vanella, G., Darvasi, E., Milanetto, A. C., Oliverius, M., Vashist, Y., Leo, M. D., Mohelnikova-Duchonova, B., Talar-Wojnarowska, R., Gheorghe, C., Petrone, M. C., Strobel, O., Arcidiacono, P. G., Vodickova, L., Szentesi, A., Capurso, G., Gajdan, L., Malleo, G., Theodoropoulos, G. E., Basso, D., Soucek, P., Brenner, H., Lawlor, R. T., Morelli, L., Ivanauskas, A., Kauffmann, E. F., Macauda, A., Gazouli, M., Archibugi, L., Nentwich, M., Loveeek, M., Cavestro, G. M., Vodicka, P., Landi, S., Tavano, F., Sperti, C., Hackert, T., Kupcinskas, J., Pezzilli, R., Andriulli, A., Pollina, L., Kreivenaite, E., Gioffreda, D., Jamroziak, K., Hegyi, P., Izbicki, J. R., Testoni, S. G. G., Zuppardo, R. A., Bozzato, D., Neoptolemos, J. P., Malats, N., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Male, Cancer Research, endocrine system diseases, Population, Quantitative Trait Loci, association study, eQTLs, pancreatic cancer, single nucleotide polymorphisms, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, medicine, Humans, Genetic Predisposition to Disease, 03.02. Klinikai orvostan, Polymorphism, Allele, education, Alleles, Aged, education.field_of_study, Carcinoma, Pancreatic Ductal, Case-Control Studies, Female, GTPase-Activating Proteins, Middle Aged, Pancreatic Neoplasms, Genome-Wide Association Study, Carcinoma, Single Nucleotide, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Pancreatic Ductal, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Pancreas
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10−10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10–6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

Published
2021

30. Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

Author

Raffaele Pezzilli, Pavel Vodicka, Andrea Párniczky, George Theodoropoulos, Renata Talar-Wojnarowska, Paolo Giorgio Arcidiacono, Ugo Boggi, Bálint Erőss, Ewa Małecka-Panas, Martin Oliverius, Daniele Campa, Rita T. Lawlor, Faik G. Uzunoglu, Maria Chiara Petrone, Livia Archibugi, Stefania Bunduc, Edita Kreivenaite, Beatrice Mohelnikova-Duchonova, Manuel Gentiluomo, Maria Liliana Piredda, Giulia Peduzzi, Thilo Hackert, Francesco Perri, Giuseppe Vanella, Olivier R. Busch, Hermann Brenner, Pavel Soucek, John P. Neoptolemos, Martin Schneider, Sabrina Gloria Giulia Testoni, Luca Morelli, Krzysztof Jamroziak, Federico Canzian, Daniela Basso, Silvia Carrara, Maria Gazouli, Juozas Kupcinskas, Konstantinos Georgiou, Xīn Gào, Claudio Pasquali, Cosimo Sperti, Evaristo Maiello, Vytautas Kiudelis, Mara Götz, Martin Loos, Gabriele Capurso, Francesca Bazzocchi, Martin Lovecek, Bas Bueno-de-Mesquita, Viktor Hlavac, Niccola Funel, Roel Vermeulen, Maarten F. Bijlsma, Anna Caterina Milanetto, Ye Lu, Giulia Martina Cavestro, Stefano Ermini, Andrea Szentesi, Jakob R. Izbicki, William Greenhalf, Francesca Tavano, Feng Guo, Marta Puzzono, Domenica Gioffreda, Péter Hegyi, Eithne Costello, Casper H.J. van Eijck, Stefano Landi, Peduzzi, G., Gentiluomo, M., Tavano, F., Arcidiacono, P. G., Ermini, S., Vodicka, P., Boggi, U., Cavestro, G. M., Capurso, G., Morelli, L., Milanetto, A. C., Pezzilli, R., Lawlor, R. T., Carrara, S., Lovecek, M., Soucek, P., Guo, F., Hackert, T., Uzunoglu, F. G., Gazouli, M., Parniczky, A., Kupcinskas, J., Bijlsma, M. F., Bueno-De-Mesquita, B., Vermeulen, R., van Eijck, C. H. J., Jamroziak, K., Talar-Wojnarowska, R., Greenhalf, W., Gioffreda, D., Petrone, M. C., Landi, S., Archibugi, L., Puzzono, M., Funel, N., Sperti, C., Piredda, M. L., Mohelnikova-Duchonova, B., Lu, Y., Hlavac, V., Gao, X., Schneider, M., Izbicki, J. R., Theodoropoulos, G., Bunduc, S., Kreivenaite, E., Busch, O. R., Malecka-Panas, E., Costello, E., Perri, F., Giulia Testoni, S. G., Vanella, G., Pasquali, C., Oliverius, M., Brenner, H., Loos, M., Gotz, M., Georgiou, K., Eross, B., Maiello, E., Szentesi, A., Bazzocchi, F., Basso, D., Neoptolemos, J. P., Hegyi, P., Kiudelis, V., Canzian, F., Campa, D., Surgery, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Center of Experimental and Molecular Medicine, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Mitochondrial DNA, Pancreatic ductal adenocarcinoma, Nuclear gene, endocrine system diseases, Epidemiology, Biology, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, SDG 3 - Good Health and Well-being, Pancreatic cancer, medicine, Humans, 03.02. Klinikai orvostan, Genetic variability, Carcinoma, Pancreatic Ductal, Case-Control Studies, Genetic Variation, Genome, Mitochondrial, Mitochondria, Pancreatic Neoplasms, Polymorphism, GENOME-WIDE ASSOCIATION, Gene, Genetics, Genome, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY, Carcinoma, Single Nucleotide, Metabolism, medicine.disease, digestive system diseases, Mitochondrial, Oncology, Pancreatic Ductal
Abstract

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10−5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Published
2021

31. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Author

Ewa Małecka-Panas, Jakob R. Izbicki, Krzysztof Jamroziak, Claudio Pasquali, Sabrina Gloria Giulia Testoni, Silvia Carrara, Livia Archibugi, Domenica Gioffreda, Francesca Tavano, Matteo Giaccherini, Gregorio Di Franco, Niccolò Napoli, Viktor Hlavac, Yogesh K. Vashist, Oliver Strobel, Martin Lovecek, Paolo Giorgio Arcidiacono, Thilo Hackert, Klara Cervena, Stefano Landi, Claudio Luchini, Andrea Szentesi, Maria Gazouli, Giulia Martina Cavestro, Daniele Campa, Gabriele Capurso, Rita T. Lawlor, Martin Oliverius, Edita Kreivenaite, Audrius Ivanauskas, Luca Morelli, Raffaele Pezzilli, Maria Chiara Petrone, Chiara Corradi, Stefania Moz, George Theodoropoulos, Michael F. Nentwich, Pavel Vodicka, Giuseppe Vanella, Hermann Brenner, Manuel Gentiluomo, John P. Neoptolemos, Cosimo Sperti, Angelo Andriulli, Ye Lu, Péter Hegyi, Cristian Gheorghe, Anna Caterina Milanetto, Pavel Soucek, László Gajdán, Erika Darvasi, Juozas Kupcinskas, Federico Canzian, Raffaella Alessia Zuppardo, Corradi, C., Gentiluomo, M., Gajdan, L., Cavestro, G. M., Kreivenaite, E., Di Franco, G., Sperti, C., Giaccherini, M., Petrone, M. C., Tavano, F., Gioffreda, D., Morelli, L., Soucek, P., Andriulli, A., Izbicki, J. R., Napoli, N., Malecka-Panas, E., Hegyi, P., Neoptolemos, J. P., Landi, S., Vashist, Y., Pasquali, C., Lu, Y., Cervena, K., Theodoropoulos, G. E., Moz, S., Capurso, G., Strobel, O., Carrara, S., Hackert, T., Hlavac, V., Archibugi, L., Oliverius, M., Vanella, G., Vodicka, P., Arcidiacono, P. G., Pezzilli, R., Milanetto, A. C., Lawlor, R. T., Ivanauskas, A., Szentesi, A., Kupcinskas, J., Testoni, S. G. G., Lovecek, M., Nentwich, M., Gazouli, M., Luchini, C., Zuppardo, R. A., Darvasi, E., Brenner, H., Gheorghe, C., Jamroziak, K., Canzian, F., and Campa, D.

Subjects
Male, Cancer Research, association study, long noncoding RNA, pancreatic cancer, single nucleotide polymorphism, Aged, Carcinoma, Pancreatic Ductal, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p15, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, MicroRNAs, Middle Aged, Pancreatic Neoplasms, RNA, Long Noncoding, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, SNP, Genetic variability, Polymorphism, Gene, Genetics, Carcinoma, Single Nucleotide, Long non-coding RNA, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, RNA, Long Noncoding
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Published
2021

32. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Author

John P. Neoptolemos, Markus W. Büchler, Jakob R. Izbicki, Ben Schöttker, Cosmeri Rizzato, Cornelia Schroeder, Salvatore Paiella, Hanneke W. M. van Laarhoven, William Greenhalf, Simona Bursi, Renata Talar-Wojnarowska, Christos Dervenis, Ludmila Vodickova, Francesca Tavano, Giulia Martina Cavestro, Thilo Hackert, Claudio Pasquali, Ewa Małecka-Panas, Gabriele Capurso, Andrea Mambrini, Daniele Campa, Andrea Padoan, Ioannis S. Papanikolaou, Raffaele Pezzilli, Péter Hegyi, Beatrice Mohelnikova-Duchonova, Federica Gemignani, Michael F. Nentwich, Pavel Vodicka, Stefano Landi, Richárd Szmola, Anna Caterina Milanetto, Eithne Costello, Rudolf Kaaks, Laura Ginocchi, Bernd Holleczek, Erika Darvasi, Verena Katzke, Evaristo Maiello, Manuel Gentiluomo, Ondrej Strouhal, Orazio Palmieri, Juozas Kupcinskas, Alice Alessandra Galeotti, Viktor Hlavac, George Theodoropoulos, Audrius Ivanauskas, Maria Gazouli, Ferenc Izbéki, Federico Canzian, Oliver Strobel, Ofure Obazee, Martin Lovecek, Timothy J. Key, Domenica Gioffreda, Pavel Soucek, Ugo Boggi, Krzysztof Jamroziak, Cosimo Sperti, Maarten F. Bijlsma, Yogesh K. Vashist, Andrea Szentesi, Hermann Brenner, Livia Archibugi, Giuseppe Vanella, Daniela Basso, Radiotherapy, Center of Experimental and Molecular Medicine, CCA - Cancer Treatment and Quality of Life, Oncology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlsma, M. F., Palmieri, O., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova-Duchonova, B., Hackert, T., Vashist, Y., Strouhal, O., Van Laarhoven, H., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malecka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropoulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szmola, R., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Buchler, M., Vodicka, P., Paiella, S., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Multifactorial Inheritance, Pancreatic disease, genetic epidemiology, Population, Single-nucleotide polymorphism, Disease, pancreas and biliary tract, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Pancreatic cancer, Internal medicine, Genetics, medicine, oncology, Humans, education, Genetics (clinical), Alleles, Early Detection of Cancer, Genetic association, education.field_of_study, business.industry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, Cohort, Female, business, Carcinoma, Pancreatic Ductal
Abstract

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Published
2020

33. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Verena Katzke, Jakob R. Izbicki, Francesca Tavano, Rita T. Lawlor, Thilo Hackert, Raffaella Alessia Zuppardo, Giulia Martina Cavestro, Federico Canzian, Frederike Dijk, Martin Oliverius, George Theodoropoulos, Pavel Soucek, Manuel Gentiluomo, Rudolf Kaaks, Erika Darvasi, Yogesh K. Vashist, Bill Greenhalf, Juozas Kupcinskas, Maurizio Lucchesi, Borislav Rusev, Andrea Szentesi, Gabriele Capurso, Ewa Małecka-Panas, Lucia Moletta, Beatrice Mohelnikova-Duchonova, Franco Bambi, Ugo Boggi, Alba Ballerini, Krzysztof Jamroziak, Ben Schöttker, Simona Bursi, Raffaele Pezzilli, Gyula Farkas, Dania Bozzato, Áron Vincze, Stefano Landi, Anna Caterina Milanetto, Péter Hegyi, Michael F. Nentwich, Laura Ginocchi, Pavel Vodicka, Stefania Moz, Ludmila Vodickova, Hermann Brenner, Olivier R. Busch, Viktor Hlavac, Audrius Ivanauskas, John P. Neoptolemos, Domenica Gioffreda, Ofure Obazee, Livia Archibugi, Nathalia A. Giese, Giuseppe Vanella, Xin Gao, Renata Talar-Wojnarowska, Angelo Andriulli, Oliver Strobel, Daniele Campa, Maria Gazouli, Pathology, CCA - Cancer biology and immunology, Surgery, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Re-generation and cancer of the digestive system, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, D., Gentiluomo, M., Obazee, O., Ballerini, A., Vodickova, L., Hegyi, P., Soucek, P., Brenner, H., Milanetto, A. C., Landi, S., Gao, X., Bozzato, D., Capurso, G., Tavano, F., Vashist, Y., Hackert, T., Bambi, F., Bursi, S., Oliverius, M., Gioffreda, D., Schottker, B., Ivanauskas, A., Mohelnikova-Duchonova, B., Darvasi, E., Pezzilli, R., Malecka-Panas, E., Strobel, O., Gazouli, M., Katzke, V., Szentesi, A., Cavestro, G. M., Farkas, G., Izbicki, J. R., Moz, S., Archibugi, L., Hlavac, V., Vincze, A., Talar-Wojnarowska, R., Rusev, B., Kupcinskas, J., Greenhalf, B., Dijk, F., Giese, N., Boggi, U., Andriulli, A., Busch, O. R., Vanella, G., Vodicka, P., Nentwich, M., Lawlor, R. T., Theodoropoulos, G. E., Jamroziak, K., Zuppardo, R. A., Moletta, L., Ginocchi, L., Kaaks, R., Neoptolemos, J. P., Lucchesi, M., and Canzian, F.

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, pancreatic cancer, early onset, Single-nucleotide polymorphism, Genome-wide association study, very early onset pancreatic cancer, Polymorphism, Single Nucleotide, 03 medical and health sciences, single nucleotide polymorphisms, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Pancreas, Genetic association, genome-wide association study, business.industry, Middle Aged, medicine.disease, Pancreatic Neoplasms, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Age of onset, business, Carcinoma, Pancreatic Ductal
Abstract

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset≤50, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved.

Published
2020

34. microRNA-mRNA network model in patients with achalasia

Author

Angelo Andriulli, Orazio Palumbo, Giuseppe Corritore, Tommaso Mazza, Anna Panza, Domenica Gioffreda, Tommaso Biagini, Anna Latiano, Fabrizio Bossa, Gabrio Bassotti, Orazio Palmieri, Salvatore Tolone, Tiziana Latiano, Massimo Carella, Antonio Merla, Giuseppina Martino, Antonello Cuttitta, Palmieri, O., Mazza, T., Bassotti, G., Merla, A., Tolone, S., Biagini, T., Cuttitta, A., Bossa, F., Martino, G., Latiano, T., Corritore, G., Gioffreda, D., Palumbo, O., Carella, M., Panza, A., Andriulli, A., and Latiano, A.

Subjects
Male, 0301 basic medicine, Physiology, mRNA, Achalasia, Disease, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, microRNA, medicine, Humans, Gene Regulatory Networks, Digital polymerase chain reaction, RNA, Messenger, ROCK2, Gene, achalasia, expression profile, Endocrine and Autonomic Systems, Gastroenterology, medicine.disease, Esophageal Achalasia, MicroRNAs, 030104 developmental biology, 030220 oncology & carcinogenesis, Gene chip analysis, Female, Transcriptome
Abstract

Background: Achalasia is a rare idiopathic disease with a complex etio-pathogenesis still unknown. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying achalasia. Methods: The investigation was performed in tissue specimens from 11 patients and five controls using the microarray technology followed by an integrated bioinformatics analysis. Key Results: One hundred and six miRNAs were significantly up-regulated and 64 were down-regulated in achalasia patients. The expression of the most 10 differential expressed miRNAs (miR-122-5p, miR-133a-3p, miR-504-5p, miR-187-3p, miR-133b, miR-200c-3p, miR-375, miR-200b-5p, miR-200b-3p, and miR203a) was confirmed by droplet digital PCR in an independent cohort. The interactions between the significant miRNAs and their targets uncovered 14 miRNA-mRNA interacting pairs with experimentally predicted genes (ie, FN1, ROCK2, DPYSL2), and 35 pairs with not experimentally target genes (ie, SULF1, MRVI1, PRKG1); all genes were involved in immune cell trafficking, skeletal and muscular system development, nervous system development macro-processes. Conclusion & Inferences: The mRNA–miRNA regulatory networks described in this study provide new insights in the genetic background of the disease, suggesting further investigations in novel pathogenic mechanisms.

Published
2019

35. Variation in genes encoding for interferon λ-3 and λ-4 in the prediction of HCV-1 treatment-induced viral clearance

Author

Raffaele Cozzolongo, Antonio Massimo Ippolito, Lydia Giannitrapani, Michele Milella, Filomena Morisco, Teresa Santantonio, Maria Rosa Valvano, Domenica Gioffreda, Angelo Andriulli, Michele Barone, Giuseppe Corritore, Pietro Gatti, Nicola Andriulli, Anna Latiano, Massimo Fasano, Giovanna D'Andrea, R. Fontana, Paolo Tundo, Maurizio Margaglione, Orazio Palmieri, Palmieri, O., Ippolito, A., Margaglione, M., Valvano, M., Gioffreda, D., Fasano, M., D'Andrea, G., Corritore, G., Milella, M., Andriulli, N., Morisco, F., Giannitrapani, L., Latiano, A., Fontana, R., Gatti, P., Tundo, P., Barone, M., Cozzolongo, R., Santantonio, T., Andriulli, A., Palmieri, Orazio, Ippolito, Antonio M, Margaglione, Maurizio, Valvano, Maria Rosa, Gioffreda, Domenica, Fasano, Massimo, D'Andrea, Giovanna, Corritore, Giuseppe, Milella, Michele, Andriulli, Nicola, Morisco, Filomena, Giannitrapani, Lydia, Latiano, Anna, Fontana, Rosanna, Gatti, Pietro, Tundo, Paolo, Barone, Michele, Cozzolongo, Raffaele, Santantonio, Teresa, and Andriulli, Angelo

Subjects
Male, Oncology, Settore MED/09 - Medicina Interna, IL28B, peg-interferon, Bioinformatics, Polyethylene Glycol, Linkage Disequilibrium, Polyethylene Glycols, Cohort Studies, IL28B/interferon lambda-3 gene, chemistry.chemical_compound, Gene Frequency, peg-interferon/ribavirin, virus diseases, Recombinant Protein, Middle Aged, Viral Load, Hepatitis C, Recombinant Proteins, Treatment Outcome, HCV, Cohort, Female, Human, Adult, medicine.medical_specialty, interferon lambda-3 gene, Locus (genetics), Single-nucleotide polymorphism, Biology, chronic hepatiti, Internal medicine, Ribavirin, medicine, Humans, SNP, Allele, Genotyping, Gene, interferon lambda-4 gene, Aged, Polymorphism, Genetic, Hepatology, Interleukins, Interferon-alpha, Interleukin, digestive system diseases, chemistry, Interferons, Cohort Studie
Abstract

Background & Aims In patients with chronic HCV-1 infection, recent evidences indicate that determination of a dinucleotide polymorphism (ss469415590, ΔG/TT) of a new gene, designated IFN λ-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sustained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. Results In the study cohort of 539 patients, 38% had SVR. The SNPs 12979860CC, rs8099917TT, and rs469415590TT/TT correlated significantly with SVR (68%, 50%, and 67%). Carriers of either the triplotype rs12979860CC_ss469415590TT/TT_rs8099917TT or the diplotype rs12979860CC_ss469415590TT/TT had the highest SVR rate (72%). In carriers of the rs12979860 T allele, neither the rs8099917 nor the ss469415590 improved the response prediction. After pooling this finding with data from previous studies, in rs12979860 T heterozygous individuals the co-presence of the rs8099917TT SNP was associated with improved response prediction. Conclusion In HCV-1 patients, the rs12979860 polymorphism appeared as the hit SNP better predicting response following peg-interferon and ribavirin treatment. Additional ss469415590 or rs8099917 genotyping had no added benefit for response prediction. In the subset of carriers of the rs12979860 T allele, genotyping of the rs8099917 SNP was unhelpful in the present investigation, but may inform clinical prediction of treatment response when our data were pooled with previous investigations.

Published
2013

36. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

Author

Ugo Boggi, Cosmeri Rizzato, Krzysztof Jamroziak, Andrea Mambrini, Gabriele Capurso, Yogesh K. Vashist, Valerio Pazienza, Christoph W. Michalski, Giulia Martina Cavestro, Keitaro Matsuo, Ewa Małecka-Panas, Jakob R. Izbicki, Harald Klüter, Timothy J. Key, Ludmila Vodickova, Vincenzo Corbo, Kenji Yamao, Domenica Gioffreda, Anna Stępień, Milena Di Leo, Willem Niesen, Audrius Ivanauskas, Cosimo Sperti, Carlo Federico Zambon, Peter Bugert, Beatrice Mohelnikova-Duchonova, Satoyo Hosono, Angelo Andriulli, Renata Talar-Wojnarowska, Maria Gazouli, John P. Neoptolemos, Franco Bambi, Francesca Tavano, Claudio Pasquali, Yasuhiro Shimizu, Manuela Pastore, Federico Canzian, Rudolf Kaaks, Daniele Campa, Gianfranco Delle Fave, Frederike Dijk, George Theodoropoulos, Raffaele Pezzilli, Paola Pacetti, Eithne Costello, Pavel Vodicka, Verena Katzke, Stefano Landi, Juozas Kupcinskas, Oliver Strobel, Martin Lovecek, Thilo Hackert, Manuel Gentiluomo, Markus W. Büchler, Pavel Soucek, Roberto Valente, Bas Bueno-de-Mesquita, Hidemi Ito, Kay-Tee Khaw, Olivier R. Busch, Daniela Basso, Campa, D, Pastore, M, Gentiluomo, M, Talar Wojnarowska, R, Kupcinskas, J, Malecka Panas, E, Neoptolemos, Jp, Niesen, W, Vodicka, P, Delle Fave, G, Bas Bueno de Mesquita, H, Gazouli, M, Pacetti, P, Di Leo, M, Ito, H, Klüter, H, Soucek, P, Corbo, V, Yamao, K, Hosono, S, Kaaks, R, Vashist, Y, Gioffreda, D, Strobel, O, Shimizu, Y, Dijk, F, Andriulli, A, Ivanauskas, A, Bugert, P, Tavano, F, Vodickova, L, Zambon, Cf, Lovecek, M, Landi, S, Key, Tj, Boggi, U, Pezzilli, R, Jamroziak, K, Mohelnikova Duchonova, B, Mambrini, A, Bambi, F, Busch, O, Pazienza, V, Valente, R, Theodoropoulos, G, Hackert, T, Capurso, G, Cavestro, GIULIA MARTINA, Pasquali, C, Basso, D, Sperti, C, Matsuo, K, Büchler, M, Khaw, Kt, Izbicki, J, Costello, E, Katzke, V, Michalski, C, Stepien, A, Rizzato, C, Canzian, F., CCA -Cancer Center Amsterdam, Pathology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Surgery

Subjects
0301 basic medicine, Pancreatic disease, CDKN2A, association study, miRSNP, pancreatic cancer, single nucleotide polymorphisms, Alleles, Asian Continental Ancestry Group, Binding Sites, Carcinoma, Pancreatic Ductal, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p18, DNA Methylation, Disease Progression, European Continental Ancestry Group, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, International Cooperation, Japan, Odds Ratio, Pancreatic Neoplasms, Prognosis, Retrospective Studies, Polymorphism, Single Nucleotide, Bioinformatics, 0302 clinical medicine, Medicine, Single Nucleotide, 3. Good health, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, Research Paper, Single-nucleotide polymorphism, White People, 03 medical and health sciences, Germline mutation, Asian People, Pancreatic cancer, Allele, Polymorphism, Cyclin-Dependent Kinase Inhibitor p16, business.industry, Carcinoma, Cancer, medicine.disease, 030104 developmental biology, Cancer research, business
Abstract

The CDKN2A(p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (OR het=1.14, 95% CI 1.01-1.27, p=0.026, ORhom =1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/Blocus could represent a genetic link between diabetes and pancreatic cancer risk.

Published
2016

37. TNF-alpha polymorphisms in primary biliary cirrhosis: a northern and southern Italian experience

Author

Pietro Invernizzi, Maria Rosa Valvano, Domenica Gioffreda, Francesca Poli, Mauro Podda, Francesca Bernuzzi, Angelo Andriulli, R. Fontana, Grazia Anna Niro, Ilaria Bianchi, Lisa Caliari, Niro, G, Poli, F, Andriulli, A, Bianchi, I, Bernuzzi, F, Caliari, L, Fontana, R, Gioffreda, D, Valvano, M, Podda, M, and Invernizzi, P

Subjects
Adult, Male, Primary biliary cirrhosi, Cirrhosis, Genotype, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, Primary biliary cirrhosis, History and Philosophy of Science, Gene Frequency, medicine, Humans, Allele, Promoter Regions, Genetic, HLA-DRB1, Allele frequency, Alleles, Aged, Biochemistry, Genetics and Molecular Biology (all), Polymorphism, Genetic, Geography, Liver disease progression, Liver Cirrhosis, Biliary, Tumor Necrosis Factor-alpha, General Neuroscience, HLA-DR Antigens, Middle Aged, medicine.disease, HLA-DR Antigen, Italy, Immunology, Disease Progression, HLA-DRB1 Chain, Female, TNF- α alleles and genotype, Human, HLA-DRB1 Chains
Abstract

Specific HLA alleles and immunoregulatory genes have been evaluated in primary biliary cirrhosis (PBC), but data are discordant. We determined whether TNF-α promoter polymorphisms (G-308A and G-238A) and alleles of HLA class II (HLA-DRB1) might be associated either with PBC occurrence and severity in Italian populations from two distinct areas. The distribution of TNF1 (G/G) genotype did not differ either between patients and controls or between patients from Northern and Southern Italy. Contrariwise, the HLA-DRB1*08 appeared positively linked to the occurrence of disease (8.4% in patients vs. 2.5% in controls, P = 0.003), whereas the HLA-DRB1*13 appeared to be protective, being more frequent in controls (12.8%) than in patients (7%) (P = 0.038). Neither positively nor negatively associated alleles of the two genomic loci had an effect on disease progression. We report a distinct genetic risk of developing PBC in the Italian population, with no interaction between the HLA and TNF alleles. © 2009 New York Academy of Sciences

Published
2009

38. Duodenal Fluid Analysis as a Rewarding Approach to Detect Low-Abundance Mutations in Biliopancreatic Cancers.

Author

Tavano F, Latiano A, Palmieri O, Gioffreda D, Latiano T, Gentile A, Tardio M, Latiano TP, Gentile M, Terracciano F, and Perri F

Subjects
Humans, Male, Female, Middle Aged, Aged, Duodenum metabolism, Duodenum pathology, Biomarkers, Tumor genetics, Liquid Biopsy methods, Adult, Cell-Free Nucleic Acids genetics, Biliary Tract Neoplasms genetics, GTP-Binding Protein alpha Subunits, Gs genetics, GTP-Binding Protein alpha Subunits, Gs metabolism, Chromogranins, Mutation, Pancreatic Neoplasms genetics, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms pathology, High-Throughput Nucleotide Sequencing methods
Abstract

Diagnosis of biliopancreatic cancers by the available serum tumor markers, imaging, and histopathological tissue specimen examination remains a challenge. Circulating cell-free DNA derived from matched pairs of secretin-stimulated duodenal fluid (DF) and plasma from 10 patients with biliopancreatic diseases and 8 control subjects was analyzed using AmpliSeq™ HD technology for Ion Torrent Next-Generation Sequencing to evaluate the potential of liquid biopsy with DF in biliopancreatic cancers. The median cfDNA concentration was greater in DF-derived than in plasma-derived samples. A total of 13 variants were detected: 11 vs. 1 were exclusive for DF relative to the plasma source, and 1 was shared between the two body fluids. According to the four-tier systems, 10 clinical tier-I-II (76.9%), 1 tier-III (7.7%), and 2 tier-IV (15.4%) variants were identified. Notably, the 11 tier-I-III variants were exclusively found in DF-derived cfDNA from five patients with biliopancreatic cancers, and were detected in seven genes (KRAS, TP53, BRAF, CDKN2A, RNF43, GNAS, and PIK3CA); 82% of the tier-I-III variants had a low abundance, with a VAF < 6%. The mutational profiling of DF seems to be a reliable and promising tool for identifying cancer-associated alterations in malignant cancers of the biliopancreatic tract.

Published
2024
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39. A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Author

Giaccherini M, Gori L, Gentiluomo M, Farinella R, Cervena K, Skieceviciene J, Dijk F, Capurso G, Vezakis A, Archibugi L, Chammas R, Hussein T, Tavano F, Hegyi P, Lovecek M, Izbicki JR, Brenner H, Mohelnikova-Duchonova B, Dell'Anna G, Kupcinskas J, Ermini S, Aoki MN, Neoptolemos JP, Gazouli M, Pasquali C, Pezzilli R, Talar-Wojnarowska R, Oliverius M, Al-Saeedi M, Lucchesi M, Furbetta N, Carrara S, van Eijck CHJ, Maleckas A, Milanetto AC, Lawlor RT, Schöttker B, Boggi U, Morelli L, Ginocchi L, Ponz de Leon Pisani R, Sperti C, Zerbi A, Arcidiacono PG, Uzunoglu FG, Bunduc S, Holleczek B, Gioffreda D, Małecka-Wojciesko E, Kiudelis M, Szentesi A, van Laarhoven HWM, Soucek P, Götz M, Erőss B, Cavestro GM, Basso D, Perri F, Landi S, Canzian F, and Campa D

Subjects
Humans, Case-Control Studies, Genome, Human, Genome-Wide Association Study, Genetic Predisposition to Disease, DNA, Polymorphism, Single Nucleotide genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal genetics
Abstract

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2023
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40. The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years' experience of association studies to understand the genetic architecture of pancreatic cancer.

Author

Campa D, Gentiluomo M, Stein A, Aoki MN, Oliverius M, Vodičková L, Jamroziak K, Theodoropoulos G, Pasquali C, Greenhalf W, Arcidiacono PG, Uzunoglu F, Pezzilli R, Luchini C, Puzzono M, Loos M, Giaccherini M, Katzke V, Mambrini A, Kiudeliene E, Federico KE, Johansen J, Hussein T, Mohelnikova-Duchonova B, van Eijck CHJ, Brenner H, Farinella R, Pérez JS, Lovecek M, Büchler MW, Hlavac V, Izbicki JR, Hackert T, Chammas R, Zerbi A, Lawlor R, Felici A, Götz M, Capurso G, Ginocchi L, Gazouli M, Kupcinskas J, Cavestro GM, Vodicka P, Moz S, Neoptolemos JP, Kunovsky L, Bojesen SE, Carrara S, Gioffreda D, Morkunas E, Abian O, Bunduc S, Basso D, Boggi U, Wlodarczyk B, Szentesi A, Vanella G, Chen I, Bijlsma MF, Kiudelis V, Landi S, Schöttker B, Corradi C, Giese N, Kaaks R, Peduzzi G, Hegyi P, Morelli L, Furbetta N, Soucek P, Latiano A, Talar-Wojnarowska R, Lindgaard SC, Dijk F, Milanetto AC, Tavano F, Cervena K, Erőss B, Testoni SG, Verhagen-Oldenampsen JHE, Małecka-Wojciesko E, Costello E, Salvia R, Maiello E, Ermini S, Sperti C, Holleczek B, Perri F, Skieceviciene J, Archibugi L, Lucchesi M, Rizzato C, and Canzian F

Subjects
Humans, Risk Factors, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms etiology, Pancreatic Neoplasms genetics
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., Competing Interests: Declaration of Competing Interest MFB has received research funding from Celgene, Frame Therapeutics, and Lead Pharma, and has acted as a consultant to Servier., (Copyright © 2023. Published by Elsevier B.V.)

Published
2023
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41. Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study.

Author

Tavano F, Gioffreda D, Fontana A, Palmieri O, Gentile A, Latiano T, Latiano A, Latiano TP, Scaramuzzi M, Maiello E, Bazzocchi F, and Perri F

Subjects
Humans, Genetic Predisposition to Disease, Mutation, Pancreatic Neoplasms, Germ-Line Mutation, Pancreatic Neoplasms genetics
Abstract

Background: Germline mutations in cancer susceptibility genes were identified in pancreatic cancer (PanC) patients with a sporadic disease and in those unselected for family cancer history., Methods: With the aim to determine the prevalence of germline predisposition genes mutations in PanC, and to evaluate whether they were associated with the presence of PanC, we profiled a custom AmpliSeq panel of 27 cancer susceptibility genes in 47 PanC patients and 51 control subjects by using the Ion Torrent PGM system., Results: Multigene panel testing identified a total of 31 variants in 27 PanC (57.4%), including variants with pathogenic/likely pathogenic effect, those of uncertain significance, and variants whose clinical significance remains currently undefined. Five patients carried more than one variant in the same gene or in different genes. Eight patients (17.0%) had at least one pathogenic/likely pathogenic variant in four main genes: CFTR (10.6%), BRCA2 (8.5%), ATM and CHEK2 (2.1%). Pathogenic/likely pathogenic mutation were identified in patients with positive PanC family history (20%) or in patients without first-degree relatives affected by PanC (13.6%). All the BRCA2 mutation carriers were unselected PanC patients. The presence of mutations in BRCA2 was significantly associated with an increased occurrence of PanC and with positive family history for endometrial cancer (p = 0.018)., Conclusions: This study confirmed the potential remarkable contribution of BRCA2 in assessing the presence of PanC. Overall our findings supported the recommendation of offering the germline testing to all the PanC patients with the intent to reduce the number of underdiagnosed carriers of mutations in predisposition genes, and not to preclude their relatives from the opportunity to benefit from surveillance programs., (© 2023. The Author(s).)

Published
2023
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42. Downexpression of miR-200c-3p Contributes to Achalasia Disease by Targeting the PRKG1 Gene.

Author

Micale L, Fusco C, Nardella G, Palmieri O, Latiano T, Gioffreda D, Tavano F, Panza A, Merla A, Biscaglia G, Gentile M, Cuttitta A, Castori M, Perri F, and Latiano A

Subjects
Humans, Binding Sites, Cell Line, Tumor, Cell Proliferation genetics, HEK293 Cells, Cyclic GMP-Dependent Protein Kinase Type I metabolism, Esophageal Achalasia genetics, MicroRNAs genetics, MicroRNAs metabolism
Abstract

Achalasia is an esophageal smooth muscle motility disorder with unknown pathogenesis. Taking into account our previous results on the downexpression of miR-200c-3p in tissues of patients with achalasia correlated with an increased expression of PRKG1 , SULF1 , and SYDE1 genes, our aim was to explore the unknown biological interaction between these genes and human miR-200c-3p and if this relation could unravel their functional role in the etiology of achalasia. To search for putative miR-200c-3p binding sites in the 3'-UTR of PRKG1 , SULF1 and SYDE1 , a bioinformatics tool was used. To test whether PRKG1 , SULF1 , and SYDE1 are targeted by miR-200c-3p, a dual-luciferase reporter assay and quantitative PCR on HEK293 and fibroblast cell lines were performed. To explore the biological correlation between PRKG1 and miR-200c-3p, an immunoblot analysis was carried out. The overexpression of miR-200c-3p reduced the luciferase activity in cells transfected with a luciferase reporter containing a fragment of the 3'-UTR regions of PRKG1 , SULF1 , and SYDE1 which included the miR-200c-3p seed sequence. The deletion of the miR-200c-3p seed sequence from the 3'-UTR fragments abrogated this reduction. A negative correlation between miR-200c-3p and PRKG1 , SULF1 , and SYDE1 expression levels was observed. Finally, a reduction of the endogenous level of PRKG1 in cells overexpressing miR-200c-3p was detected. Our study provides, for the first time, functional evidence about the PRKG1 gene as a direct target and SULF1 and SYDE1 as potential indirect substrates of miR-200c-3p and suggests the involvement of NO/cGMP/PKG signaling in the pathogenesis of achalasia.

Published
2022
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43. Adherence to Gluten-Free Diet Restores Alpha Diversity in Celiac People but the Microbiome Composition Is Different to Healthy People.

Author

Palmieri O, Castellana S, Bevilacqua A, Latiano A, Latiano T, Panza A, Fontana R, Ippolito AM, Biscaglia G, Gentile A, Gioffreda D, Decina I, Tricarico M, Sinigaglia M, Corbo MR, Mazza T, Perri F, and Lamacchia C

Subjects
Diet, Gluten-Free, Dysbiosis microbiology, Humans, Celiac Disease, Gastrointestinal Microbiome, Microbiota
Abstract

Celiac disease (CD) is an autoimmune disease with the destruction of small intestinal villi, which occurs in genetically predisposed individuals. At the present moment, a gluten-free diet (GFD) is the only way to restore the functionality of gut mucosa. However, there is an open debate on the effects of long-term supplementation through a GFD, because some authors report an unbalance in microbial taxa composition., Methods: For microbiome analysis, fecal specimens were collected from 46 CD individuals in GFD for at least 2 years and 30 specimens from the healthy controls (HC). Data were analyzed using an ensemble of software packages: QIIME2, Coda-lasso, Clr-lasso, Selbal, PICRUSt2, ALDEx2, dissimilarity-overlap analysis, and dysbiosis detection tests., Results: The adherence to GFD restored the alpha biodiversity of the gut microbiota in celiac people but microbial composition at beta diversity resulted as different to HC. The microbial composition of the CD subjects was decreased in a number of taxa, namely Bifidobacterium longum and several belonging to Lachnospiraceae family, whereas Bacteroides genus was found to be more abundant. Predicted metabolic pathways among the CD bacterial communities revealed an important role in tetrapyrrole biosynthesis., Conclusions: CD patients in GFD had a non-dysbiotic microbial composition for the crude alpha diversity metrics. We found significant differences in beta diversity, in certain taxon, and pathways between subjects with inactive CD in GFD and controls. Collectively, our data may suggest the development of new GFD products by modulating the gut microbiota through diet, supplements of vitamins, and the addition of specific prebiotics.

Published
2022
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44. Healthy and pro-inflammatory gut ecology plays a crucial role in the digestion and tolerance of a novel Gluten Friendly™ bread in celiac subjects: a randomized, double blind, placebo control in vivo study.

Author

Andriulli A, Bevilacqua A, Palmieri O, Latiano A, Fontana R, Gioffreda D, Castellana S, Mazza T, Panza A, Menzaghi C, Grandone E, di Mauro L, Decina I, Tricarico M, Musaico D, Mäki M, Isola J, Popp A, Taavela J, Petruzzi L, Sinigaglia M, Rosaria Corbo M, and Lamacchia C

Subjects
Adult, Age Factors, Double-Blind Method, Female, Humans, Male, Middle Aged, Young Adult, Bread, Celiac Disease metabolism, Diet, Gluten-Free methods, Gastrointestinal Microbiome physiology, Inflammation metabolism
Abstract

Gluten Friendly™ (GF) is a new gluten achieved through a physicochemical process applied to wheat kernels. The goal of this research was to assess the in vivo effects of Gluten Friendly™ bread on celiac gut mucosa and microbiota. In a double-blind placebo-controlled intervention study, 48 celiac disease (CD) patients were randomized into 3 groups to eat 100 g of bread daily, containing different doses (0; 3 g; 6 g) of GF for 12 weeks. The small-bowel morphology (VH/CrD), intraepithelial densities of CD3+, celiac serology, MUC2, CB1, gut permeability, proinflammatory cytokines, gluten in stools, symptoms, and gut microbial composition were assessed. All 48 CD subjects experienced no symptoms. K-means analysis evidenced celiac subjects clustering around unknown parameters independent of GF dosage: K1 35%; K2 30%; K3 35%. VH/CrD significantly decreased in K1 and K2. VH/CrD did not correlate with IEL increase in K2. 33-mer was not detected in 47% and 73% of patients in both K1 and K2, respectively. VH/CrD and IEL did not change significantly and strongly correlated with the absence of 33-mer in K3. Inflammation and VH/CrD decrease are strongly related with the presence of proinflammatory species at the baseline. A boost in probiotic, butyrate-producing genera, is strongly related with GF tolerance at the end of the trial. Our research suggests that a healthy and proinflammatory ecology could play a crucial role in the digestion and tolerance of the new gluten molecule in celiac subjects. However, GF can be completely digested by gut microbiota of CD subjects and shapes it toward gut homeostasis by boosting healthy butyrate-producing populations. The clinical trial registry number is NCT03137862 (https://clinicaltrials.gov).

Published
2022
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45. Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Author

Lu Y, Gentiluomo M, Macauda A, Gioffreda D, Gazouli M, Petrone MC, Kelemen D, Ginocchi L, Morelli L, Papiris K, Greenhalf W, Izbicki JR, Kiudelis V, Mohelníková-Duchoňová B, Bueno-de-Mesquita B, Vodicka P, Brenner H, Diener MK, Pezzilli R, Ivanauskas A, Salvia R, Szentesi A, Aoki MN, Németh BC, Sperti C, Jamroziak K, Chammas R, Oliverius M, Archibugi L, Ermini S, Novák J, Kupcinskas J, Strouhal O, Souček P, Cavestro GM, Milanetto AC, Vanella G, Neoptolemos JP, Theodoropoulos GE, van Laarhoven HWM, Mambrini A, Moz S, Kala Z, Loveček M, Basso D, Uzunoglu FG, Hackert T, Testoni SGG, Hlaváč V, Andriulli A, Lucchesi M, Tavano F, Carrara S, Hegyi P, Arcidiacono PG, Busch OR, Lawlor RT, Puzzono M, Boggi U, Guo F, Małecka-Panas E, Capurso G, Landi S, Talar-Wojnarowska R, Strobel O, Gao X, Vashist Y, Campa D, and Canzian F

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 (p<10 -5 ) compared with the additive effects (p>10 -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., 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, Gentiluomo, Macauda, Gioffreda, Gazouli, Petrone, Kelemen, Ginocchi, Morelli, Papiris, Greenhalf, Izbicki, Kiudelis, Mohelníková-Duchoňová, Bueno-de-Mesquita, Vodicka, Brenner, Diener, Pezzilli, Ivanauskas, Salvia, Szentesi, Aoki, Németh, Sperti, Jamroziak, Chammas, Oliverius, Archibugi, Ermini, Novák, Kupcinskas, Strouhal, Souček, Cavestro, Milanetto, Vanella, Neoptolemos, Theodoropoulos, van Laarhoven, Mambrini, Moz, Kala, Loveček, Basso, Uzunoglu, Hackert, Testoni, Hlaváč, Andriulli, Lucchesi, Tavano, Carrara, Hegyi, Arcidiacono, Busch, Lawlor, Puzzono, Boggi, Guo, Małecka-Panas, Capurso, Landi, Talar-Wojnarowska, Strobel, Gao, Vashist, Campa and Canzian.)

Published
2021
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46. Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk.

Author

Peduzzi G, Gentiluomo M, Tavano F, Arcidiacono PG, Ermini S, Vodicka P, Boggi U, Cavestro GM, Capurso G, Morelli L, Milanetto AC, Pezzilli R, Lawlor RT, Carrara S, Lovecek M, Souček P, Guo F, Hackert T, Uzunoğlu FG, Gazouli M, Párniczky A, Kupcinskas J, Bijlsma MF, Bueno-de-Mesquita B, Vermeulen R, van Eijck CHJ, Jamroziak K, Talar-Wojnarowska R, Greenhalf W, Gioffreda D, Petrone MC, Landi S, Archibugi L, Puzzono M, Funel N, Sperti C, Piredda ML, Mohelnikova-Duchonova B, Lu Y, Hlaváč V, Gao X, Schneider M, Izbicki JR, Theodoropoulos G, Bunduc S, Kreivenaite E, Busch OR, Małecka-Panas E, Costello E, Perri F, Testoni SGG, Vanella G, Pasquali C, Oliverius M, Brenner H, Loos M, Götz M, Georgiou K, Erőss B, Maiello E, Szentesi A, Bazzocchi F, Basso D, Neoptolemos JP, Hegyi P, Kiudelis V, Canzian F, and Campa D

Subjects
Carcinoma, Pancreatic Ductal genetics, Case-Control Studies, Genetic Variation, Genome, Mitochondrial, Humans, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal metabolism, Mitochondria metabolism, Pancreatic Neoplasms metabolism
Abstract

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported., Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software., Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk ( P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes ( TERT , SUGCT , and SURF1 ) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance ( P = 0.05/1588 = 3.1 × 10 -5 )., Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk., Impact: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk., (©2021 American Association for Cancer Research.)

Published
2021
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47. 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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48. Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

Author

Pistoni L, Gentiluomo M, Lu Y, López de Maturana E, Hlavac V, Vanella G, Darvasi E, Milanetto AC, Oliverius M, Vashist Y, Di Leo M, Mohelnikova-Duchonova B, Talar-Wojnarowska R, Gheorghe C, Petrone MC, Strobel O, Arcidiacono PG, Vodickova L, Szentesi A, Capurso G, Gajdán L, Malleo G, Theodoropoulos GE, Basso D, Soucek P, Brenner H, Lawlor RT, Morelli L, Ivanauskas A, Kauffmann EF, Macauda A, Gazouli M, Archibugi L, Nentwich M, Loveček M, Cavestro GM, Vodicka P, Landi S, Tavano F, Sperti C, Hackert T, Kupcinskas J, Pezzilli R, Andriulli A, Pollina L, Kreivenaite E, Gioffreda D, Jamroziak K, Hegyi P, Izbicki JR, Testoni SGG, Zuppardo RA, Bozzato D, Neoptolemos JP, Malats N, Canzian F, and Campa D

Subjects
Aged, Alleles, Case-Control Studies, Female, GTPase-Activating Proteins genetics, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Pancreatic Neoplasms genetics, Quantitative Trait Loci
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2021
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49. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Author

Corradi C, Gentiluomo M, Gajdán L, Cavestro GM, Kreivenaite E, Di Franco G, Sperti C, Giaccherini M, Petrone MC, Tavano F, Gioffreda D, Morelli L, Soucek P, Andriulli A, Izbicki JR, Napoli N, Małecka-Panas E, Hegyi P, Neoptolemos JP, Landi S, Vashist Y, Pasquali C, Lu Y, Cervena K, Theodoropoulos GE, Moz S, Capurso G, Strobel O, Carrara S, Hackert T, Hlavac V, Archibugi L, Oliverius M, Vanella G, Vodicka P, Arcidiacono PG, Pezzilli R, Milanetto AC, Lawlor RT, Ivanauskas A, Szentesi A, Kupcinskas J, Testoni SGG, Lovecek M, Nentwich M, Gazouli M, Luchini C, Zuppardo RA, Darvasi E, Brenner H, Gheorghe C, Jamroziak K, Canzian F, and Campa D

Subjects
Aged, Case-Control Studies, Computational Biology methods, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Carcinoma, Pancreatic Ductal genetics, Cyclin-Dependent Kinase Inhibitor p15 genetics, MicroRNAs genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide, RNA, Long Noncoding genetics
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10 -9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism., (© 2021 UICC.)

Published
2021
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50. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

Author

Galeotti AA, Gentiluomo M, Rizzato C, Obazee O, Neoptolemos JP, Pasquali C, Nentwich M, Cavestro GM, Pezzilli R, Greenhalf W, Holleczek B, Schroeder C, Schöttker B, Ivanauskas A, Ginocchi L, Key TJ, Hegyi P, Archibugi L, Darvasi E, Basso D, Sperti C, Bijlsma MF, Palmieri O, Hlavac V, Talar-Wojnarowska R, Mohelnikova-Duchonova B, Hackert T, Vashist Y, Strouhal O, van Laarhoven H, Tavano F, Lovecek M, Dervenis C, Izbéki F, Padoan A, Małecka-Panas E, Maiello E, Vanella G, Capurso G, Izbicki JR, Theodoropoulos GE, Jamroziak K, Katzke V, Kaaks R, Mambrini A, Papanikolaou IS, Szmola R, Szentesi A, Kupcinskas J, Bursi S, Costello E, Boggi U, Milanetto AC, Landi S, Gazouli M, Vodickova L, Soucek P, Gioffreda D, Gemignani F, Brenner H, Strobel O, Büchler M, Vodicka P, Paiella S, Canzian F, and Campa D

Subjects
ABO Blood-Group System genetics, Alleles, Carcinoma, Pancreatic Ductal diagnosis, Carcinoma, Pancreatic Ductal genetics, Early Detection of Cancer, Female, Gene Frequency, Humans, Male, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide, Risk Assessment, Multifactorial Inheritance
Abstract

Background: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection., Objective: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score., Methods: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes., Results: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10 -10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10 -8 , highest vs lowest quintile of the weighted multifactorial score)., Conclusion: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population., Competing Interests: Competing interests: MFB has received research funding from Celgene. HvL has acted as a consultant for Celgene, and Eli Lilly and Company, Nordic Pharma Group and Philips, and has received research grants from Amgen, Bayer Schering Pharma, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, MSD, Nordic Pharma Group, Philips and Roche Pharmaceuticals., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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