Search

Your search keyword '"Vashist Y"' showing total 125 results
Start Over Author "Vashist Y" Publication Year Range Last 10 years
125 results on '"Vashist Y"'

1. Dissecting the genetic heterogeneity of gastric cancer

Author

Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schuller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J., Mayr, A., Schroder, J., Hillmer, A. M., Heider, D., Lordick, F., Perez-Aisa, A., Campo, R., Espinel, J., Geijo, F., Thomson, C., Bujanda, L., Sopena, F., Lanas, A., Pellise, M., Pauligk, C., Goetze, T. O., Zelck, C., Reingruber, J., Hassanin, E., Elbe, P., Alsabeah, S., Lindblad, M., Nilsson, M., Kreuser, N., Thieme, R., Tavano, F., Pastorino, Roberta, Arzani, D., Persiani, Roberto, Jung, J. -O., Nienhuser, H., Ott, K., Schumann, R. R., Kumpf, O., Burock, S., Arndt, V., Jakubowska, A., Lawniczak, M., Moreno, V., Martin, V., Kogevinas, M., Pollan, M., Dabrowska, J., Salas, A., Cussenot, O., Boland-Auge, A., Daian, D., Deleuze, J. -F., Salvi, E., Teder-Laving, M., Tomasello, G., Ratti, M., Senti, C., De Re, V., Steffan, A., Holscher, A. H., Messerle, K., Bruns, C. J., Sivins, A., Bogdanova, I., Skieceviciene, J., Arstikyte, J., Moehler, M., Lang, H., Grimminger, P. P., Kruschewski, M., Vassos, N., Schildberg, C., Lingohr, P., Ridwelski, K., Lippert, H., Fricker, N., Krawitz, P., Hoffmann, Christian Pieter, Nothen, M. M., Veits, L., Izbicki, J. R., Mostowska, A., Martinon-Torres, F., Cusi, D., Adolfsson, R., Cancel-Tassin, G., Hoblinger, A., Rodermann, E., Ludwig, M., Keller, G., Metspalu, A., Brenner, H., Heller, J., Neef, M., Schepke, M., Dumoulin, F. L., Hamann, L., Cannizzaro, Rino, Ghidini, Maria Candida, Plassmann, D., Geppert, M., Malfertheiner, P., Gehlen, O., Skoczylas, T., Majewski, M., Lubinski, J., Palmieri, O., Boccia, Stefania, Latiano, A., Aragones, N., Schmidt, T., Dinis-Ribeiro, M., Medeiros, R., Al-Batran, S. -E., Leja, M., Kupcinskas, J., Garcia-Gonzalez, M. A., Venerito, M., Schumacher, J., Pastorino R. (ORCID:0000-0001-5013-0733), Persiani R. (ORCID:0000-0002-1537-5097), Hoffmann P., Cannizzaro R., Ghidini M., Boccia S. (ORCID:0000-0002-1864-749X), Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schuller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J., Mayr, A., Schroder, J., Hillmer, A. M., Heider, D., Lordick, F., Perez-Aisa, A., Campo, R., Espinel, J., Geijo, F., Thomson, C., Bujanda, L., Sopena, F., Lanas, A., Pellise, M., Pauligk, C., Goetze, T. O., Zelck, C., Reingruber, J., Hassanin, E., Elbe, P., Alsabeah, S., Lindblad, M., Nilsson, M., Kreuser, N., Thieme, R., Tavano, F., Pastorino, Roberta, Arzani, D., Persiani, Roberto, Jung, J. -O., Nienhuser, H., Ott, K., Schumann, R. R., Kumpf, O., Burock, S., Arndt, V., Jakubowska, A., Lawniczak, M., Moreno, V., Martin, V., Kogevinas, M., Pollan, M., Dabrowska, J., Salas, A., Cussenot, O., Boland-Auge, A., Daian, D., Deleuze, J. -F., Salvi, E., Teder-Laving, M., Tomasello, G., Ratti, M., Senti, C., De Re, V., Steffan, A., Holscher, A. H., Messerle, K., Bruns, C. J., Sivins, A., Bogdanova, I., Skieceviciene, J., Arstikyte, J., Moehler, M., Lang, H., Grimminger, P. P., Kruschewski, M., Vassos, N., Schildberg, C., Lingohr, P., Ridwelski, K., Lippert, H., Fricker, N., Krawitz, P., Hoffmann, Christian Pieter, Nothen, M. M., Veits, L., Izbicki, J. R., Mostowska, A., Martinon-Torres, F., Cusi, D., Adolfsson, R., Cancel-Tassin, G., Hoblinger, A., Rodermann, E., Ludwig, M., Keller, G., Metspalu, A., Brenner, H., Heller, J., Neef, M., Schepke, M., Dumoulin, F. L., Hamann, L., Cannizzaro, Rino, Ghidini, Maria Candida, Plassmann, D., Geppert, M., Malfertheiner, P., Gehlen, O., Skoczylas, T., Majewski, M., Lubinski, J., Palmieri, O., Boccia, Stefania, Latiano, A., Aragones, N., Schmidt, T., Dinis-Ribeiro, M., Medeiros, R., Al-Batran, S. -E., Leja, M., Kupcinskas, J., Garcia-Gonzalez, M. A., Venerito, M., Schumacher, J., Pastorino R. (ORCID:0000-0001-5013-0733), Persiani R. (ORCID:0000-0002-1537-5097), Hoffmann P., Cannizzaro R., Ghidini M., and Boccia S. (ORCID:0000-0002-1864-749X)

Abstract

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me

Published
2023

7. 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
Full Text
View/download PDF

8. 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

9. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., Buas, M.F., Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., and Buas, M.F.

Abstract

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access), Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Published
2021

10. 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

11. 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

13. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., Canzian, F., Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., and Canzian, F.

Subjects
Male, Cancer Research, pancreatic cancer, Genes, BRCA2, I157T, Polymorphism, Single Nucleotide, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, BRCA2 Protein, K3326X, PANDoRA consortium, rs11571833, rs17879961, Oncology, Pancreatic cancer, Middle Aged, Pancreatic Neoplasms, Checkpoint Kinase 2, Case-Control Studies, Female, Carcinoma, Pancreatic Ductal
Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Published
2018

14. 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

15. 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

16. 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

17. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Author

Böhmer, A.C., Hecker, J., Schröder, J., Gharahkhani, P., May, A., Gerges, C., Anders, M., Becker, J., Hess, T., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Fuchs, C., Izbicki, J.R., Hölscher, A.H., Dietrich, A., Moulla, Y., Lyros, O., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismüller, J., Moebus, S., Knapp, M., Neuhaus, H., Rösch, T., Ell, C., Nöthen, M.M., Whiteman, D.C., Tomlinson, I., Jankowski, J., Fitzgerald, R.C., Palles, C., Vaughan, T.L., Gockel, I., Thrift, A.P., Fier, H., Schumacher, J., Böhmer, A.C., Hecker, J., Schröder, J., Gharahkhani, P., May, A., Gerges, C., Anders, M., Becker, J., Hess, T., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Fuchs, C., Izbicki, J.R., Hölscher, A.H., Dietrich, A., Moulla, Y., Lyros, O., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismüller, J., Moebus, S., Knapp, M., Neuhaus, H., Rösch, T., Ell, C., Nöthen, M.M., Whiteman, D.C., Tomlinson, I., Jankowski, J., Fitzgerald, R.C., Palles, C., Vaughan, T.L., Gockel, I., Thrift, A.P., Fier, H., and Schumacher, J.

Abstract

Contains fulltext : 220009.pdf (Publisher’s version ) (Closed access), BACKGROUND: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. METHODS: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. RESULTS: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (r(g) = 0.13, P = 2 × 10(-04)) and a r(g) of 0.12 between WHR and BE/EA (P = 1 × 10(-02)). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (r(g) = 0.17, P = 1.2 × 10(-03)), and WHR and EA in males (r(g) = 0.18, P = 1.51 × 10(-02)). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10(-03)) and WHR and BE/EA risk variants (P = 2 × 10(-02)). CONCLUSIONS: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. IMPACT: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

Published
2020

18. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author

Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., Thrift, A.P., Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., and Thrift, A.P.

Abstract

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access), BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Published
2020

19. 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

20. Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma

Author

Becker, J., May, A., Gerges, C., Anders, M., Veits, L., Weise, K., Czamara, D., Lyros, O., Manner, H., Terheggen, G., Venerito, M., Noder, T., Mayershofer, R., Hofer, J., Karch, H., Ahlbrand, C., Arras, M., Hofer, S., Mangold, E., Heilmann-Heimbach, S., Heinrichs, S., Hess, T., Kiesslich, R., Izbicki, J., Hoelscher, A., Bollschweiler, E., Malfertheiner, P., Lang, H., Moehler, M., Lorenz, D., Müller-Myhsok, B., Ott, K., Schmidt, T., Whiteman, D., Vaughan, T., Noethen, M., Hackelsberger, A., Schumacher, B., Pech, O., Vashist, Y., Vieth, M., Weismueller, J., Neuhaus, H., Roesch, T., Ell, C., Gockel, I., and Schumacher, J.

Subjects
Adult, Male, esophageal adenocarcinoma, Adolescent, Esophageal Neoplasms, Genotype, FOXP1, Adenocarcinoma, BARX1, Polymorphism, Single Nucleotide, Young Adult, Odds Ratio, Humans, Genetic Predisposition to Disease, FOXF1, Alleles, Genetic Association Studies, Cancer Biology, Homeodomain Proteins, Forkhead Transcription Factors, Repressor Proteins, Genetic Loci, genetic association study, Case-Control Studies, Female, Genome-Wide Association Study, Transcription Factors
Abstract

The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P< 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P

Published
2015

21. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study

Author

Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., Thrift, A.P., Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., and Thrift, A.P.

Abstract

Contains fulltext : 215282.pdf (publisher's version ) (Closed access), BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Published
2019

22. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O, Archibugi, L, Andriulli, A, Soucek, P, Małecka-Panas, E, Ivanauskas, A, Johnson, T, Gazouli, M, Pausch, T, Lawlor, R T, Cavestro, G M, Milanetto, A C, Di Leo, M, Pasquali, C, Hegyi, P, Szentesi, A, Radu, C E, Gheorghe, C, Theodoropoulos, G E, Bergmann, F, Brenner, H, Vodickova, L, Katzke, V, Campa, D, Strobel, O, Kaiser, J, Pezzilli, R, Federici, F, Mohelnikova-Duchonova, B, Boggi, U, Lemstrova, R, Johansen, J S, Bojesen, S E, Chen, I, Jensen, B V, Capurso, G, Pazienza, V, Dervenis, C, Sperti, C, Mambrini, A, Hackert, T, Kaaks, R, Basso, D, Talar-Wojnarowska, R, Maiello, E, Izbicki, J R, Cuk, K, Saum, K U, Cantore, M, Kupcinskas, J, Palmieri, O, Delle Fave, G, Landi, S, Salvia, R, Fogar, P, Vashist, Y K, Scarpa, A, Vodicka, P, Tjaden, C, Iskierka-Jazdzewska, E, Canzian, F, Obazee, O, Archibugi, L, Andriulli, A, Soucek, P, Małecka-Panas, E, Ivanauskas, A, Johnson, T, Gazouli, M, Pausch, T, Lawlor, R T, Cavestro, G M, Milanetto, A C, Di Leo, M, Pasquali, C, Hegyi, P, Szentesi, A, Radu, C E, Gheorghe, C, Theodoropoulos, G E, Bergmann, F, Brenner, H, Vodickova, L, Katzke, V, Campa, D, Strobel, O, Kaiser, J, Pezzilli, R, Federici, F, Mohelnikova-Duchonova, B, Boggi, U, Lemstrova, R, Johansen, J S, Bojesen, S E, Chen, I, Jensen, B V, Capurso, G, Pazienza, V, Dervenis, C, Sperti, C, Mambrini, A, Hackert, T, Kaaks, R, Basso, D, Talar-Wojnarowska, R, Maiello, E, Izbicki, J R, Cuk, K, Saum, K U, Cantore, M, Kupcinskas, J, Palmieri, O, Delle Fave, G, Landi, S, Salvia, R, Fogar, P, Vashist, Y K, Scarpa, A, Vodicka, P, Tjaden, C, Iskierka-Jazdzewska, E, and Canzian, F

Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Published
2019

23. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, A.P. Wolpin, B.M. Risch, H.A. Stolzenberg-Solomon, R.Z. Mocci, E. Zhang, M. Canzian, F. Childs, E.J. Hoskins, J.W. Jermusyk, A. Zhong, J. Chen, F. Albanes, D. Andreotti, G. Arslan, A.A. Babic, A. Bamlet, W.R. Beane-Freeman, L. Berndt, S.I. Blackford, A. Borges, M. Borgida, A. Bracci, P.M. Brais, L. Brennan, P. Brenner, H. Bueno-De-Mesquita, B. Buring, J. Campa, D. Capurso, G. Cavestro, G.M. Chaffee, K.G. Chung, C.C. Cleary, S. Cotterchio, M. Dijk, F. Duell, E.J. Foretova, L. Fuchs, C. Funel, N. Gallinger, S. Gaziano, J.M.M. Gazouli, M. Giles, G.G. Giovannucci, E. Goggins, M. Goodman, G.E. Goodman, P.J. Hackert, T. Haiman, C. Hartge, P. Hasan, M. Hegyi, P. Helzlsouer, K.J. Herman, J. Holcatova, I. Holly, E.A. Hoover, R. Hung, R.J. Jacobs, E.J. Jamroziak, K. Janout, V. Kaaks, R. Khaw, K.-T. Klein, E.A. Kogevinas, M. Kooperberg, C. Kulke, M.H. Kupcinskas, J. Kurtz, R.J. Laheru, D. Landi, S. Lawlor, R.T. Lee, I.-M. Lemarchand, L. Lu, L. Malats, N. Mambrini, A. Mannisto, S. Milne, R.L. Mohelníková-Duchoňová, B. Neale, R.E. Neoptolemos, J.P. Oberg, A.L. Olson, S.H. Orlow, I. Pasquali, C. Patel, A.V. Peters, U. Pezzilli, R. Porta, M. Real, F.X. Rothman, N. Scelo, G. Sesso, H.D. Severi, G. Shu, X.-O. Silverman, D. Smith, J.P. Soucek, P. Sund, M. Talar-Wojnarowska, R. Tavano, F. Thornquist, M.D. Tobias, G.S. Van Den Eeden, S.K. Vashist, Y. Visvanathan, K. Vodicka, P. Wactawski-Wende, J. Wang, Z. Wentzensen, N. White, E. Yu, H. Yu, K. Zeleniuch-Jacquotte, A. Zheng, W. Kraft, P. Li, D. Chanock, S. Obazee, O. Petersen, G.M. Amundadottir, L.T.

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: Rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. © 2018 The Author(s).

Published
2018

24. 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
Full Text
View/download PDF

25. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., primary, Archibugi, L., additional, Andriulli, A., additional, Soucek, P., additional, Małecka-Panas, E., additional, Ivanauskas, A., additional, Johnson, T., additional, Gazouli, M., additional, Pausch, T., additional, Lawlor, R. T., additional, Cavestro, G. M., additional, Milanetto, A. C., additional, Di Leo, M., additional, Pasquali, C., additional, Hegyi, P., additional, Szentesi, A., additional, Radu, C. E., additional, Gheorghe, C., additional, Theodoropoulos, G. E., additional, Bergmann, F., additional, Brenner, H., additional, Vodickova, L., additional, Katzke, V., additional, Campa, D., additional, Strobel, O., additional, Kaiser, J., additional, Pezzilli, R., additional, Federici, F., additional, Mohelnikova-Duchonova, B., additional, Boggi, U., additional, Lemstrova, R., additional, Johansen, J. S., additional, Bojesen, S. E., additional, Chen, I., additional, Jensen, B. V., additional, Capurso, G., additional, Pazienza, V., additional, Dervenis, C., additional, Sperti, C., additional, Mambrini, A., additional, Hackert, T., additional, Kaaks, R., additional, Basso, D., additional, Talar-Wojnarowska, R., additional, Maiello, E., additional, Izbicki, J. R., additional, Cuk, K., additional, Saum, K. U., additional, Cantore, M., additional, Kupcinskas, J., additional, Palmieri, O., additional, Delle Fave, G., additional, Landi, S., additional, Salvia, R., additional, Fogar, P., additional, Vashist, Y. K., additional, Scarpa, A., additional, Vodicka, P., additional, Tjaden, C., additional, Iskierka-Jazdzewska, E., additional, and Canzian, F., additional

Published
2019
Full Text
View/download PDF

28. Follow-up of a CFTR association with Barrett's esophagus and esophageal adenocarcinoma

Author

Boehmer, A. C., Schueller, V., Hess, T., Becker, J., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Schmidt, C., Izbicki, J. R., Hoelscher, A. H., Schumacher, B., Mayershofer, R., Pech, O., Vashist, Y., Weismueller, J., Knapp, M., Moebus, S., Peters, W. H. M., Neuhaus, H., Roesch, T., Noethen, M. M., Gockel, I., Schumacher, J., Boehmer, A. C., Schueller, V., Hess, T., Becker, J., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Schmidt, C., Izbicki, J. R., Hoelscher, A. H., Schumacher, B., Mayershofer, R., Pech, O., Vashist, Y., Weismueller, J., Knapp, M., Moebus, S., Peters, W. H. M., Neuhaus, H., Roesch, T., Noethen, M. M., Gockel, I., and Schumacher, J.

Published
2018

29. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, Amundadottir, LT, Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, and Amundadottir, LT

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

Published
2018

30. Germline genetic variants and risk of Barrett's esophagus and esophageal adenocarcinoma: a large scale meta-analysis of genome-wide association studies

Author

Palles, C, Tomlinson, I, Chegwidden, L, Gharahkhani, P, MacGregor, S, Vaughan, T, Schumacher, J, Jankowski, J, Fitzgerald, R, Gockel, I, Buas, M, May, A, Gerges, C, Anders, M, Becker, J, Kreuser, N, Noder, T, Venerito, M, Veits, L, Schmidt, T, Manner, H, Schmidt, C, Hess, T, Böhmer, A, Izbicki, J, Hölscher, A, Lang, H, Lorenz, D, Schumacher, B, Hackelsberger, A, Mayershofer, R, Pech, O, Vashist, Y, Ott, K, Vieth, M, Weismüller, J, Nöthen, M, Attwood, S, Barr, H, de Caestecker, J, Harrison, R, Love, S, MacDonald, D, Moayyed, P, Prenen, H, Watson, R, Iyer, P, Anderson, L, Bernstein, L, Chow, W, Hardie, L, Lagergren, J, Liu, G, Risch, H, Wu, A, Ye, W, Bird, N, Shaheen, N, Gammon, M, Corley, D, Caldas, C, Moebus, S, Knapp, M, Peters, W, Neuhaus, H, Rösch, T, Ell, C, Pharaoh, P, and Whiteman, D

Abstract

Background Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA. Methods Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways. Findings We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P Interpretation The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.

Published
2016

31. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, M. Wang, Z. Obazee, O. Jia, J. Childs, E.J. Hoskins, J. Figlioli, G. Mocci, E. Collins, I. Chung, C.C. Hautman, C. Arslan, A.A. Beane-Freeman, L. Bracci, P.M. Buring, J. Duell, E.J. Gallinger, S. Giles, G.G. Goodman, G.E. Goodman, P.J. Kamineni, A. Kolonel, L.N. Kulke, M.H. Malats, N. Olson, S.H. Sesso, H.D. Visvanathan, K. White, E. Zheng, W. Abnet, C.C. Albanes, D. Andreotti, G. Brais, L. Bas Bueno-de-Mesquita, H. Basso, D. Berndt, S.I. Boutron-Ruault, M.-C. Bijlsma, M.F. Brenner, H. Burdette, L. Campa, D. Caporaso, N.E. Capurso, G. Cavestro, G.M. Cotterchio, M. Costello, E. Elena, J. Boggi, U. Michael Gaziano, J. Gazouli, M. Giovannucci, E.L. Goggins, M. Gross, M. Haiman, C.A. Hassan, M. Helzlsouer, K.J. Hu, N. Hunter, D.J. Iskierka-Jazdzewska, E. Jenab, M. Kaaks, R. Key, T.J. Khaw, K.-T. Klein, E.A. Kogevinas, M. Krogh, V. Kupcinskas, J. Kurtz, R.C. Landi, M.T. Landi, S. Marchand, L.L. Mambrini, A. Mannisto, S. Milne, R.L. Neale, R.E. Oberg, A.L. Panico, S. Patel, A.V. Peeters, P.H.M. Peters, U. Pezzilli, R. Porta, M. Purdue, M. Ramón Quiros, J. Riboli, E. Rothman, N. Scarpa, A. Scelo, G. Shu, X.-O. Silverman, D.T. Soucek, P. Strobel, O. Sund, M. Malecka-Panas, E. Taylor, P.R. Tavano, F. Travis, R.C. Thornquist, M. Tjønneland, A. Tobias, G.S. Trichopoulos, D. Vashist, Y. Vodicka, P. Wactawski-Wende, J. Wentzensen, N. Yu, H. Yu, K. Zeleniuch-Jacquotte, A. Kooperberg, C. Risch, H.A. Jacobs, E.J. Li, D. Fuchs, C. Hoover, R. Hartge, P. Chanock, S.J. Petersen, G.M. Stolzenberg-Solomon, R.S. Wolpin, B.M. Kraft, P. Klein, A.P. Canzian, F. Amundadottir, L.T.

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

32. 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

34. Gemeinsame genetische Ätiologie des Barrett-Ösophagus/-Karzinoms und der Adipositas

Author

Böhmer, AC, additional, Hecker, J, additional, May, A, additional, Gerges, C, additional, Venerito, M, additional, Schmidt, T, additional, Schmidt, C, additional, Manner, H, additional, Vashist, Y, additional, Benner, U, additional, Meyershofer, R, additional, Anders, M, additional, Vieth, M, additional, Hess, T, additional, Becker, J, additional, Knapp, M, additional, Moebus, S, additional, Nöthen, M, additional, Dietrich, A, additional, Thieme, R, additional, Ebigbo, A, additional, Messmann, H, additional, Peters, WH, additional, Büchler, MW, additional, Izbicki, JR, additional, Hölscher, AH, additional, Schumacher, B, additional, Weismüller, J, additional, Neuhaus, H, additional, Rösch, T, additional, Ell, C, additional, Gockel, I, additional, Fier, H, additional, and Schumacher, J, additional

Published
2017
Full Text
View/download PDF

35. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, Amundadottir, LT, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, and Amundadottir, LT

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

39. Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767)

Author

Keck, Tobias, primary, Wellner, U. F., additional, Bahra, M., additional, Klein, F., additional, Sick, O., additional, Niedergethmann, M., additional, Wilhelm, T. J., additional, Farkas, S. A., additional, Börner, T., additional, Bruns, C., additional, Kleespies, A., additional, Kleeff, J., additional, Mihaljevic, A. L., additional, Uhl, W., additional, Chromik, A., additional, Fendrich, V., additional, Heeger, K., additional, Padberg, W., additional, Hecker, A., additional, Neumann, U. P., additional, Junge, K., additional, Kalff, J. C., additional, Glowka, T. R., additional, Werner, J., additional, Knebel, P., additional, Piso, P., additional, Mayr, M., additional, Izbicki, J., additional, Vashist, Y., additional, Bronsert, P., additional, Bruckner, T., additional, Limprecht, R., additional, Diener, M. K., additional, Rossion, I., additional, Wegener, I., additional, and Hopt, U. T., additional

Published
2016
Full Text
View/download PDF

41. Pankreatogastrostomie versus Pankreatojejunostomie – Ergebnisse einer multizentrischen randomisierten Studie (RECOPANC)

Author

Wellner, U, primary, Keck, T, additional, Bahra, M, additional, Klein, F, additional, Sick, O, additional, Niedergethmann, M, additional, Wilhelm, T, additional, Farkas, S, additional, Börner, T, additional, Bruns, C, additional, Keelspies, A, additional, Kleeff, J, additional, Mihaljevic, A, additional, Uhl, W, additional, Chromik, A, additional, Fendrich, V, additional, Heeger, K, additional, Padberg, W, additional, Hecker, A, additional, Neumann, U, additional, Junge, K, additional, Kalff, J, additional, Glowka, T, additional, Werner, J, additional, Knebel, P, additional, Piso, P, additional, Mayr, M, additional, Izbicki, J, additional, Vashist, Y, additional, Bronsert, P, additional, Bruckner, T, additional, Limprecht, T, additional, Diener, M, additional, Rossion, I, additional, Wegener, I, additional, and Hopt, U, additional

Published
2015
Full Text
View/download PDF

42. 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
Full Text
View/download PDF

43. 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

44. 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

45. 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

46. 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

47. 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
Full Text
View/download PDF

48. 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

49. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.

Subjects
0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract

Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

50. The Aging Stomach: Clinical Implications of H. pylori Infection in Older Adults-Challenges and Strategies for Improved Management.

Author

Skokowski J, Vashist Y, Girnyi S, Cwalinski T, Mocarski P, Antropoli C, Brillantino A, Boccardi V, Goyal A, Ciarleglio FA, Almohaimeed MA, De Luca R, Abou-Mrad A, Marano L, Oviedo RJ, and Januszko-Giergielewicz B

Subjects
Humans, Aged, Stomach microbiology, Stomach pathology, Anti-Bacterial Agents therapeutic use, Probiotics therapeutic use, Helicobacter Infections complications, Helicobacter Infections drug therapy, Helicobacter Infections therapy, Helicobacter pylori pathogenicity, Aging
Abstract

Aging is a multifactorial biological process characterized by a decline in physiological function and increasing susceptibility to various diseases, including malignancies and gastrointestinal disorders. Helicobacter pylori ( H. pylori ) infection is highly prevalent among older adults, particularly those in institutionalized settings, contributing to conditions such as atrophic gastritis, peptic ulcer disease, and gastric carcinoma. This review examines the intricate interplay between aging, gastrointestinal changes, and H. pylori pathogenesis. The age-associated decline in immune function, known as immunosenescence, exacerbates the challenges of managing H. pylori infection. Comorbidities and polypharmacy further increase the risk of adverse outcomes in older adults. Current clinical guidelines inadequately address the specific needs of the geriatric population, who are disproportionately affected by antibiotic resistance, heightened side effects, and diagnostic complexities. This review focuses on recent advancements in understanding H. pylori infection among older adults, including epidemiology, diagnostics, therapeutic strategies, and age-related gastric changes. Diagnostic approaches must consider the physiological changes that accompany aging, and treatment regimens need to be carefully tailored to balance efficacy and tolerability. Emerging strategies, such as novel eradication regimens and adjunctive probiotic therapies, show promise for improving treatment outcomes. However, significant knowledge gaps persist regarding the impact of aging on H. pylori pathogenesis and treatment efficacy. A multidisciplinary approach involving gastroenterologists, geriatricians, and other specialists is crucial to providing comprehensive care for this vulnerable population. Future research should focus on refining diagnostic and therapeutic protocols to bridge these gaps, ultimately enhancing clinical outcomes and reducing the burden of H. pylori -associated diseases in the aging population.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results