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8. Acute diverticulitis in immunocompromised patients: evidence from an international multicenter observational registry (Web-based International Register of Emergency Surgery and Trauma, Wires-T)

Author

Tartaglia, D., Cremonini, C., Annunziata, E., Catena, F., Sartelli, M., Kirkpatrick, A. W., Musetti, S., Strambi, S., Chiarugi, M., Coccolini, F., Salvetti, F., Fugazzola, P., Ceresoli, M., Benedetti, F., Elisa, N. G., Litvin, A., Lostoridis, E., Ahmed, A. Y. Y. M., Manatakis, D., Negoi, I., Ioannidis, O., Uzunoglu, M. Y., Tochie, J. N., Cillara, N., Tomadze, G., Bala, M., Isik, A., Fonseca, V. C., Bellanova, G., Ghannam, W., Yalkin, O., Garcia, F. H., Altintoprak, F., Hadzhiev, D., Chirica, M., Zese, M., Balalis, D., Cui, Y., Luppi, D., Romeo, L., Muratore, A., Lunghi, E. G., Yovtchev, Y., Dimitrov, E., Nikolopoulos, I., Omerovic, M., Zizzo, M., Ugoletti, L., Costa, G., Scalzone, R., Perrone, S., Occhionorelli, S., Nardi, M., Gubbiotti, F., Muhtaroglu, A., Scaramuzzo, R., Corte, H., Yanez, C., Zakaria, A. D., Seretis, C., Gelmini, R., Pappalardo, V., Paratore, F., Sydorchuk, R., Mulita, F., Kara, Y., Toma, E. A., Vailas, M., Sotiropoulou, M., Elbahnasawy, M., Sibilla, M. G., Martines, G., Goksoy, B., Parini, D., Zaghi, C., Podda, M., Osipov, A., Brisinda, G., Gambino, G., Doklestic, L. A. K., Loncar, Z., Micic, D., Lesevic, I., D'Agostino, F., Garzali, I. U., Caicedo, Y., Marcela, L., Marin, P. A. G., Perivoliotis, K., Ntentas, I., Kuptsov, A., Chowdhury, S., Patel, T., Tartaglia, D, Cremonini, C, Annunziata, E, Catena, F, Sartelli, M, Kirkpatrick, A, Musetti, S, Strambi, S, Chiarugi, M, Coccolini, F, Salvetti, F, Fugazzola, P, Ceresoli, M, Benedetti, F, Elisa, N, Litvin, A, Lostoridis, E, Ahmed, A, Manatakis, D, Negoi, I, Ioannidis, O, Uzunoglu, M, Tochie, J, Cillara, N, Tomadze, G, Bala, M, Isik, A, Fonseca, V, Bellanova, G, Ghannam, W, Yalkin, O, Garcia, F, Altintoprak, F, Hadzhiev, D, Chirica, M, Zese, M, Balalis, D, Cui, Y, Luppi, D, Romeo, L, Muratore, A, Lunghi, E, Yovtchev, Y, Dimitrov, E, Nikolopoulos, I, Omerovic, M, Zizzo, M, Ugoletti, L, Costa, G, Scalzone, R, Perrone, S, Occhionorelli, S, Nardi, M, Gubbiotti, F, Muhtaroglu, A, Scaramuzzo, R, Corte, H, Yanez, C, Zakaria, A, Seretis, C, Gelmini, R, Pappalardo, V, Paratore, F, Sydorchuk, R, Mulita, F, Kara, Y, Toma, E, Vailas, M, Sotiropoulou, M, Elbahnasawy, M, Sibilla, M, Martines, G, Goksoy, B, Parini, D, Zaghi, C, Podda, M, Osipov, A, Brisinda, G, Gambino, G, Doklestic, L, Loncar, Z, Micic, D, Lesevic, I, D'Agostino, F, Garzali, I, Caicedo, Y, Marcela, L, Marin, P, Perivoliotis, K, Ntentas, I, Kuptsov, A, Chowdhury, S, and Patel, T

Subjects
Medical therapy, Acute diverticuliti, Gastroenterology, Acute diverticulitis, Surgery, Immunocompromised
Abstract

Background Immunocompromised patients with acute diverticulitis are at increased risk of morbidity and mortality. The aim of this study was to compare clinical presentations, types of treatment, and outcomes between immunocompromised and immunocompetent patients with acute diverticulitis. Methods We compared the data of patients with acute diverticulitis extracted from the Web-based International Registry of Emergency Surgery and Trauma (WIRES-T) from January 2018 to December 2021. First, two groups were identified: medical therapy (A) and surgical therapy (B). Each group was divided into three subgroups: nonimmunocompromised (grade 0), mildly to moderately (grade 1), and severely immunocompromised (grade 2). Results Data from 482 patients were analyzed—229 patients (47.5%) [M:F = 1:1; median age: 60 (24–95) years] in group A and 253 patients (52.5%) [M:F = 1:1; median age: 71 (26–94) years] in group B. There was a significant difference between the two groups in grade distribution: 69.9% versus 38.3% for grade 0, 26.6% versus 51% for grade 1, and 3.5% versus 10.7% for grade 2 (p p = 0.027) was more common in higher grades of immunodeficiency. Patients with grade 2 needed longer hospitalization (p = 0.005). In group B, a similar condition was found in terms of severe sepsis (p = 0.002), quick Sequential Organ Failure Assessment score > 2 (p = 0.0002), and Mannheim Peritonitis Index (p = 0.010). A Hartmann’s procedure is mainly performed in grades 1–2 (p p = 0.047). Mortality was higher in the immunocompromised patients (p = 0.002). Conclusions Immunocompromised patients with acute diverticulitis present with a more severe clinical picture. When surgery is required, immunocompromised patients mainly undergo a Hartmann’s procedure. Postoperative morbidity and mortality are, however, higher in immunocompromised patients, who also require a longer hospital stay.

Published
2023

9. Colorectal neoplastic emergencies in immunocompromised patients: preliminary result from the Web-based International Register of Emergency Surgery and Trauma (WIRES-T trial)

Author

Coccolini F., Mazzoni A., Cremonini C., Cobuccio L., Pucciarelli M., Vetere G., Borelli B., Strambi S., Musetti S., Miccoli M., Cremolini C., Salvetti F., Fugazzola P., Ceresoli M., Elisa N. G., Litvin A., Lostoridis E., Ahmed A. Y. Y. M., Manatakis D., Negoi I., Ioannidis O., Uzunoglu M. Y., Tochie J. N., Cillara N., Tomadze G., Bala M., Isik A., Fonseca V. C., Bellanova G., Ghannam W., Yalkin O., Garcia F. H., Altintoprak F., Hadzhiev D., Chirica M., Zese M., Balalis D., Cui Y., Luppi D., Romeo L., Muratore A., Lunghi E. G., Yovtchev Y., Nikolopoulos I., Omerovic M., Zizzo M., Ugoletti L., Costa G., Scalzone R., Perrone S., Occhionorelli S., Nardi M., Gubbiotti F., Catena F., Muhtaroglu A., Scaramuzzo R., Corte H., Yanez C., Zakaria A. D., Seretis C., Gelmini R., Pappalardo V., Paratore F., Sydorchuk R., Mulita F., Kara Y., Toma E. A., Vailas M., Sotiropoulou M., Benedetti F., Elbahnasawy M., Sibilla M. G., Martines G., Goksoy B., Parini D., Zaghi C., Podda M., Osipov A., Brisinda G., Gambino G., Akhmeteli L., Doklestic K., Loncar Z., Micic D., Lesevic I., D'Agostino F., Garzali I. U., Caicedo Y., Marcela L., Marin P. A. G., Perivoliotis K., Ntentas I., Kuptsov A., Dimitrov E., Chowdhury S., Patel T., Sartelli M., Tartaglia D., Chiarugi M., Coccolini, F, Mazzoni, A, Cremonini, C, Cobuccio, L, Pucciarelli, M, Vetere, G, Borelli, B, Strambi, S, Musetti, S, Miccoli, M, Cremolini, C, Salvetti, F, Fugazzola, P, Ceresoli, M, Elisa, N, Litvin, A, Lostoridis, E, Ahmed, A, Manatakis, D, Negoi, I, Ioannidis, O, Uzunoglu, M, Tochie, J, Cillara, N, Tomadze, G, Bala, M, Isik, A, Fonseca, V, Bellanova, G, Ghannam, W, Yalkin, O, Garcia, F, Altintoprak, F, Hadzhiev, D, Chirica, M, Zese, M, Balalis, D, Cui, Y, Luppi, D, Romeo, L, Muratore, A, Lunghi, E, Yovtchev, Y, Nikolopoulos, I, Omerovic, M, Zizzo, M, Ugoletti, L, Costa, G, Scalzone, R, Perrone, S, Occhionorelli, S, Nardi, M, Gubbiotti, F, Catena, F, Muhtaroglu, A, Scaramuzzo, R, Corte, H, Yanez, C, Zakaria, A, Seretis, C, Gelmini, R, Pappalardo, V, Paratore, F, Sydorchuk, R, Mulita, F, Kara, Y, Toma, E, Vailas, M, Sotiropoulou, M, Benedetti, F, Elbahnasawy, M, Sibilla, M, Martines, G, Goksoy, B, Parini, D, Zaghi, C, Podda, M, Osipov, A, Brisinda, G, Gambino, G, Akhmeteli, L, Doklestic, K, Loncar, Z, Micic, D, Lesevic, I, D'Agostino, F, Garzali, I, Caicedo, Y, Marcela, L, Marin, P, Perivoliotis, K, Ntentas, I, Kuptsov, A, Dimitrov, E, Chowdhury, S, Patel, T, Sartelli, M, Tartaglia, D, and Chiarugi, M

Subjects
Survival, Colon, Emergency, Acute care, Surgery, Morbidity, Mortality, Immunosuppression, Cancer
Abstract

Association of advanced age, neoplastic disease and immunocompromission (IC) may lead to surgical emergencies. Few data exist about this topic. Present study reports the preliminary data from the WIRES-T trial about patients managed for colorectal neoplastic emergencies in immunocompromised patients. The required data were taken from a prospective observational international register. The study was approved by the Ethical Committee with approval n. 17575; ClinicalTrials.gov Identifier: NCT03643718. 839 patients were collected; 753 (80.7%) with mild–moderate IC and 86 (10.3%) with severe. Median age was 71.9 years and 73 years, respectively, in the two groups. The causes of mild–moderate IC were reported such malignancy (753–100%), diabetes (103–13.7%), malnutrition (26–3.5%) and uremia (1–0.1%), while severe IC causes were steroids treatment (14–16.3%); neutropenia (7–8.1%), malignancy on chemotherapy (71–82.6%). Preoperative risk classification were reported as follow: mild–moderate: ASA 1–14 (1.9%); ASA 2–202 (26.8%); ASA 3–341 (45.3%); ASA 4–84 (11.2%); ASA 5–7 (0.9%); severe group: ASA 1-1 patient (1.2%); ASA 2–16 patients (18.6%); ASA 3–41 patients (47.7%); ASA 4–19 patients (22.1%); ASA 5–3 patients (3.5%); lastly, ASA score was unavailable for 105 cases (13.9%) in mild–moderate group and in 6 cases (6.9%) in severe group. All the patients enrolled underwent urgent/emergency surgery Damage control approach with open abdomen was adopted in 18 patients. Mortality was 5.1% and 12.8%, respectively, in mild–moderate and severe groups. Long-term survival data: in mild–moderate disease-free survival (median, IQR) is 28 (10–91) and in severe IC, it is 21 (10–94). Overall survival (median, IQR) is 44 (18–99) and 26 (20–90) in mild–moderate and severe, respectively; the same is for post-progression survival (median, IQR) 29 (16–81) and 28, respectively. Univariate and multivariate analyses showed as the only factor influencing mortality in mild–moderate and severe IC is the ASA score. Colorectal neoplastic emergencies in immunocompromised patients are more frequent in elderly. Sigmoid and right colon are the most involved. Emergency surgery is at higher risk of complication and mortality; however, management in dedicated emergency surgery units is necessary to reduce disease burden and to optimize results by combining oncological and acute care principles. This approach may improve outcomes to obtain clinical advantages for patients like those observed in elective scenario. Lastly, damage control approach seems feasible and safe in selected patients.

Published
2023

25. Harmonization and validation of diagnostic protocols for the detection of grapevine viruses covered by phytosanitary rules

Author

Faggioli, F., Anaclerio, F., Angelini, E., Antonelli, M. G., Bertazzon, N., Bianchi, G., Bianchedi, P., Bianco, P.A., Botti, S., Bragagna, P., Cardoni, M., Casati, P., Credi, R., De Luca, E., Durante, G., Gianinazzi, C., Gambino, G., Gualandri, V., Luison, D., Luvisi, A., Malossini, U., Mannini, F., Saldarelli, P., Terlizzi, F., Triolo, E., Trisciuzzi, N., and Barba, M.

Published
2013

27. Genomic Designing for Biotic Stress Resistant Grapevine

Author

Vezzulli, S., Gramaje, D., Tello, J., Gambino, G., Bettinelli, P., Pirrello, C., Schwandner, A., Barba, P., Angelini, E., Anfora, G., Mazzoni, V., Pozzebon, A., Palomares-Rius, J. E., Martínez-Diz, M. P., Toffolatti, S. L., De Lorenzis, G., De Paoli, E., Perrone, I., D’Incà, E., Zenoni, S., Wilmink, J., Lacombe, T., Crespan, M., Walker, M. A., Bavaresco, L., De la Fuente, M., Fennell, A., Tornielli, G. B., Forneck, A., Ibáñez, J., Hausmann &amp, and Reisch, B. I.

Subjects
resistance, Genotyping, Settore AGR/07 - GENETICA AGRARIA, Genotyping Molecular breeding Pathogen Pest Phenotyping R-loci Resistance Vitis, Biotic stress, Pathogen, Phenotyping, Molecular breeding, Pest, Vitis, grapevine, Biotic stress, resistance, R-loci, grapevine
Abstract

Grapevines are challenged by a range of diseases and pests, causing economic losses and requiring often costly approaches to mitigate damage. Public interest in reducing the use of chemicals is a related challenge, along with climate change. Yet, the Vitis gene pool provides vast resources for the development of genetic resistance in rootstock and scion cultivars. Traditional breeding approaches have made great strides in the development of adaptive traits, and recent access to ‘omic technologies has further facilitated the identification of useful loci along with rapid trait introgression from wild species. Moreover, marker technologies are now used to stack multiple genes for the same trait into a single genotype, a heretofore barely accessible technology. Genomic technologies are also impacting germplasm characterization, and thereby facilitating “Breeding by Design” approaches. Genetic transformation and gene-editing technologies are also applicable for both cultivar improvement as well as functional studies of genes. The landscape for acceptance of new resistant cultivars is complex and with wine grapes, subject to high degrees of regulation especially in the European Union. With rootstocks, as well as table/raisin grapes, gaining acceptance in the marketplace for new cultivars developed through either traditional or marker-assisted approaches is routine. Yet even in the highly regulated EU environment, the adoption of new wine cultivars of interspecific origins is beginning to take place in both traditional wine growing regions as well as non-traditional regions nearby.

Published
2022

37. Stress responses and epigenomic instability mark the loss of somatic embryogenesis competence in grapevine

Author

Dal Santo S., De Paoli E., Pagliarani C., Amato A., Celii M., Boccacci P., Zenoni S., Gambino G., and Perrone I

Subjects
embryogenic competence, food and beverages, transposon silencing, Vitis vinifera (grapevine), somatic embryogenesis, transcriptome
Abstract

Somatic embryogenesis (SE) represents the most appropriate tool for next-generation breeding methods in woody plants such as grapevine (Vitis vinifera L.). However, in this species the SE competence is strongly genotype dependent and the molecular basis of this phenomenon is poorly understood. We explored the genetic and epigenetic basis of SE in grapevine by profiling the transcriptome, epigenome and small RNAome of undifferentiated, embryogenic, and non-embryogenic callus tissues derived from two genotypes differing in competence for SE, Sangiovese and Cabernet Sauvignon. During the successful formation of embryonic callus, we observed the upregulation of epigenetic-related transcripts and short interfering RNAs in association with DNA hypermethylation at transposable elements in both varieties. Nevertheless, the switch to non-embryonic development matched the incomplete reinforcement of transposon silencing, and the evidence of such effect was more apparent in the recalcitrant Cabernet Sauvignon. Transcriptomic differences between the two genotypes were maximized already at early stage of culture where the recalcitrant variety expressed a broad panel of genes related to stress responses and secondary metabolism. Our data provide a different angle on the SE molecular dynamics that can be exploited to leverage SE as a biotechnological tool for fruit crop breeding.

Published
2021

40. Molecular modeling of interactions between L-lysine and functionalized quartz surfaces

Author

Gambino, G.. Laura, Grassi, Antonio, and Marletta, Giovanni

Subjects
Lysine -- Chemical properties, Lysine -- Structure, Quartz -- Chemical properties, Molecules -- Models, Molecules -- Methods, Chemicals, plastics and rubber industries
Abstract

Molecular modeling techniques are used to investigate the interaction of L-lysine in aqueous medium with silanol and methyl sites onto quartz substrates. The structure of water shells around L-lysine molecules is strongly affected by the relative hydrophilic/hydrophobic character of the surfaces, where the order is almost completely lost for partially hydrophilic surfaces, while well-defined hydration shells around L-lysine are obtained for hydrophobic surfaces.

Published
2006

43. Correction to :β adrenergic receptor kinase C-terminal peptide gene-therapy improves ß2-adrenergic receptor-dependent neoangiogenesis after hindlimb ischemia (Journal of Pharmacology and Experimental Therapeutics (2016) 356:2 (503–513) DOI: 10.1124/jpet.115.228411)

Author

Cannavo A., Liccardo D., Lymperopoulos A., Gambino G., D'Amico M. L., Rengo F., Koch W. J., Leosco D., Ferrara N., Rengo G., Cannavo, A., Liccardo, D., Lymperopoulos, A., Gambino, G., D'Amico, M. L., Rengo, F., Koch, W. J., Leosco, D., Ferrara, N., and Rengo, G.

Abstract

In the above article [Cannavo A, Liccardo D, Lymperopoulos A, Gambino G, D’Amico ML, Rengo F, Koch WJ, Leosco D, Ferrara N, and Rengo G (2016) J Pharmacol Exp Ther 356(2): 503–513; DOI: 10.1124/jpet.115.228411], the following funding information was omitted: This work was funded by the National Institutes of Health [Grant R37 HL061690]. The authors regret this error and any inconvenience it may have caused.

Published
2019

44. Anthelmintic activity of Stevia multiaristata extract against Echinococcus granulosus sensu stricto.

Author

Albani, C. M., Borgo, J., Fabbri, J., Pensel, P., Fasciani, L., Elso, O., Papademetrio, D., Grasso, D., Paladini, A., Beer, M. F., Farias, N. E., Elissondo, N., Gambino, G., Zoppi, J., Sülsen, V., and Elissondo, M. C.

Subjects
ECHINOCOCCUS granulosus, LEISHMANIASIS, ESSENTIAL oils, STEVIA, DITERPENES
Abstract

Keywords: Anti-parasitic treatment; cystic echinococcosis; phytotherapy; plant extract EN Anti-parasitic treatment cystic echinococcosis phytotherapy plant extract 519 528 10 03/29/22 20220401 NES 220401 Introduction Cystic echinococcosis (CE) is a worldwide zoonotic disease caused by the larval stage of the parasite I Echinococcus granulosus sensu lato i ( I s.l. i ) which provokes long-term infections in humans and animals, being a serious public health problem (Pavletic I et al i ., 2017). Based on the World Health Organization Informal Working Group on Echinococcosis (WHO-IWGE) classification of cyst stages by imaging-based techniques, four treatment options have been suggested: percutaneous-aspiration-injection and re-aspiration (PAIR), surgery, anti-parasitic therapy with benzimidazoles (BZM) and a watch-and-wait approach for inactive cysts (Siles-Lucas I et al i ., 2018). For I in vitro i studies involving Huh7 cells, the I S. multiaristata i extract (10 mg) was sequentially resuspended in 20 I i L of DMSO, 40 I i L of ethanol 96% and finally, 40 I i L of deionized water, giving a solution of 100 mg mL SP -1 sp . We found that the I S. multiaristata i extract caused both an I in vitro i effect on protoscoleces and cysts and also an I in vivo i therapeutic effect. [Extracted from the article]

Published
2022
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45. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).

Published
2020
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