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2. Reference standards for gene fusion molecular assays on cytological samples: an international validation study

Author

Malapelle, U, Pepe, F, Pisapia, P, Altimari, A, Bellevicine, C, Brunnström, H, Bruno, R, Büttner, R, Cirnes, L, De Andrea, C, de Biase, D, Dumur, C, Ericson Lindquist, K, Fontanini, G, Gautiero, E, Gentien, D, Hofman, P, Hofman, V, Iaccarino, A, Lozano, M, Mayo-de-Las-Casas, C, Merkelbach-Bruse, S, Pagni, F, Roman, R, Schmitt, F, Siemanowski, J, Roy-Chowdhuri, S, Tallini, G, Tresserra, F, Vander Borght, S, Vielh, P, Vigliar, E, Vita, G, Weynand, B, Rosell, R, Molina Vila, M, Troncone, G, Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Altimari, Annalisa, Bellevicine, Claudio, Brunnström, Hans, Bruno, Rossella, Büttner, Reinhard, Cirnes, Luis, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Ericson Lindquist, Kajsa, Fontanini, Gabriella, Gautiero, Eugenio, Gentien, David, Hofman, Paul, Hofman, Veronique, Iaccarino, Antonino, Lozano, Maria Dolores, Mayo-de-Las-Casas, Clara, Merkelbach-Bruse, Sabine, Pagni, Fabio, Roman, Ruth, Schmitt, Fernando C, Siemanowski, Janna, Roy-Chowdhuri, Sinchita, Tallini, Giovanni, Tresserra, Francesc, Vander Borght, Sara, Vielh, Philippe, Vigliar, Elena, Vita, Giulia Anna Carmen, Weynand, Birgit, Rosell, Rafael, Molina Vila, Miguel Angel, Troncone, Giancarlo, Malapelle, U, Pepe, F, Pisapia, P, Altimari, A, Bellevicine, C, Brunnström, H, Bruno, R, Büttner, R, Cirnes, L, De Andrea, C, de Biase, D, Dumur, C, Ericson Lindquist, K, Fontanini, G, Gautiero, E, Gentien, D, Hofman, P, Hofman, V, Iaccarino, A, Lozano, M, Mayo-de-Las-Casas, C, Merkelbach-Bruse, S, Pagni, F, Roman, R, Schmitt, F, Siemanowski, J, Roy-Chowdhuri, S, Tallini, G, Tresserra, F, Vander Borght, S, Vielh, P, Vigliar, E, Vita, G, Weynand, B, Rosell, R, Molina Vila, M, Troncone, G, Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Altimari, Annalisa, Bellevicine, Claudio, Brunnström, Hans, Bruno, Rossella, Büttner, Reinhard, Cirnes, Luis, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Ericson Lindquist, Kajsa, Fontanini, Gabriella, Gautiero, Eugenio, Gentien, David, Hofman, Paul, Hofman, Veronique, Iaccarino, Antonino, Lozano, Maria Dolores, Mayo-de-Las-Casas, Clara, Merkelbach-Bruse, Sabine, Pagni, Fabio, Roman, Ruth, Schmitt, Fernando C, Siemanowski, Janna, Roy-Chowdhuri, Sinchita, Tallini, Giovanni, Tresserra, Francesc, Vander Borght, Sara, Vielh, Philippe, Vigliar, Elena, Vita, Giulia Anna Carmen, Weynand, Birgit, Rosell, Rafael, Molina Vila, Miguel Angel, and Troncone, Giancarlo

Abstract

AIMS: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. METHODS: Cell lines harbouring EML4(13)-ALK(20) and SLC34A2(4)-ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. RESULTS: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. CONCLUSIONS: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.

Published
2023

5. MA05.04 Multiplex Phenotyping Reveals Spatial Immune Patterns in NSCLC

Author

Backman, M., primary, Elfving, H., additional, Brunnström, H., additional, Mattsson, J.S.M., additional, Isaksson, J., additional, La Fleur, L., additional, Kärre, K., additional, Pontén, F., additional, Lamberg, K., additional, Lindskog, C., additional, Gulyas, M., additional, Strell, C., additional, Botling, J., additional, Mezheyeuski, A., additional, and Micke, P., additional

Published
2022
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9. Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Author

Rosenberger, A., Tozzi, V., Bickeböller, H., Hung, R.J., Christiani, D.C., Caporaso, N.E., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Aldrich, M.C., Tardon, A., Fernández-Tardón, G., Rennert, G., Field, J.K., Davies, M., Liloglou, T., Kiemeney, L.A., Lazarus, P., Haugen, A., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Duell, E.J., Arnold, S.M., Brunnström, H., Melander, O., Goodman, G.E., Chen, C., Doherty, J.A., Teare, M.D., Cox, A., Woll, P.J., Risch, A., Muley, T.R., Johansson, M., Brennan, P., Landi, M.T., Shete, S.S., and Amos, C.I.

Abstract

Background\ud \ud Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand.\ud \ud \ud \ud Results\ud \ud Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2).\ud \ud \ud \ud Conclusion\ud \ud We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.

Published
2022

10. FP16.04 A Nationwide Population-Based Mapping of Mutations and Gene Fusions in Lung Cancer Among Never-Smokers

Author

Salomonsson, A., primary, Jönsson, M., additional, Behndig, A., additional, Bergman, B., additional, Botling, J., additional, Brandén, E., additional, Koyi, H., additional, Brunnström, H., additional, De Petris, L., additional, Helenius, G., additional, Hussein, A., additional, Johansson, M., additional, Kentson, M., additional, Lamberg, K., additional, Lewensohn, R., additional, Mager, U., additional, Monsef, N., additional, Ortiz-Villalon, C., additional, Patthey, A., additional, Sundh, J., additional, Vikström, A., additional, Wagenius, G., additional, Staaf, J., additional, and Planck, M., additional

Published
2021
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11. Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization

Author

Zhou, W., Liu, G., Hung, R.J., Haycock, P.C., Aldrich, M.C., Andrew, A.S., Arnold, S.M., Bickeböller, H., Bojesen, S.E., Brennan, P., Brunnström, H., Melander, O., Caporaso, N.E., Landi, M.T., Chen, C, Goodman, G.E., Christiani, D.C., Cox, A, Field, J.K., Johansson, M., Kiemeney, L.A.L.M., Lam, S., Lazarus, P., Marchand, L. Le, Rennert, G., Risch, A., Schabath, M.B., Shete, S.S., Tardón, A., Zienolddiny, S., Shen, H., Amos, C.I., Zhou, W., Liu, G., Hung, R.J., Haycock, P.C., Aldrich, M.C., Andrew, A.S., Arnold, S.M., Bickeböller, H., Bojesen, S.E., Brennan, P., Brunnström, H., Melander, O., Caporaso, N.E., Landi, M.T., Chen, C, Goodman, G.E., Christiani, D.C., Cox, A, Field, J.K., Johansson, M., Kiemeney, L.A.L.M., Lam, S., Lazarus, P., Marchand, L. Le, Rennert, G., Risch, A., Schabath, M.B., Shete, S.S., Tardón, A., Zienolddiny, S., Shen, H., and Amos, C.I.

Abstract

Contains fulltext : 232176.pdf (Publisher’s version ) (Closed access), At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10(-4) ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR(MVMR) = 1.28, 95% CI = 1.06-1.55, P(MVMR) = .011), and an inverse effect on lung adenocarcinoma (OR(MVMR) = 0.86, 95% CI = 0.77-0.96, P(MVMR) = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR(UVMR) = 1.19, 95% CI = 1.01-1.40, P(UVMR) = .036), but this effect disappeared after adjustment of smoking (OR(MVMR) = 1.02, 95% CI = 0.90-1.16, P(MVMR) = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

Published
2021

12. A Nationwide Population-Based Mapping of Mutations and Gene Fusions in Lung Cancer Among Never-Smokers

Author

Salomonsson, A., Jönsson, M., Behndig, A., Bergman, B., Botling, J., Brandén, E., Koyi, H., Brunnström, H., De Petris, L., Helenius, Gisela, Hussein, A., Johansson, M., Kentson, M., Lamberg, K., Lewensohn, R., Mager, U., Monsef, N., Ortiz-Villalon, C., Patthey, A., Sundh, Josefin, Vikström, A., Wagenius, G., Staaf, J., Planck, M., Salomonsson, A., Jönsson, M., Behndig, A., Bergman, B., Botling, J., Brandén, E., Koyi, H., Brunnström, H., De Petris, L., Helenius, Gisela, Hussein, A., Johansson, M., Kentson, M., Lamberg, K., Lewensohn, R., Mager, U., Monsef, N., Ortiz-Villalon, C., Patthey, A., Sundh, Josefin, Vikström, A., Wagenius, G., Staaf, J., and Planck, M.

Published
2021
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14. Comprehensive analysis of RNA binding motif protein 3 (RBM3) in non-small cell lung cancer

Author

Salomonsson, A., Micke, P., Mattsson, J. S. M., La Fleur, L., Isaksson, J., Jönsson, M., Nodin, B., Botling, J., Uhlén, Mathias, Jirström, K., Staaf, J., Planck, M., Brunnström, H., Salomonsson, A., Micke, P., Mattsson, J. S. M., La Fleur, L., Isaksson, J., Jönsson, M., Nodin, B., Botling, J., Uhlén, Mathias, Jirström, K., Staaf, J., Planck, M., and Brunnström, H.

Abstract

Aims High expression of the RNA-binding motif protein 3 (RBM3) correlates with improved prognosis in several major types of cancer. The aim of the present study was to examine the prognostic value of RBM3 protein and mRNA expression in non-small cell lung cancer (NSCLC). Methods and results Immunohistochemical expression of RBM3 was evaluated in surgically treated NSCLC from two independent patient populations (n = 213 and n = 306). Staining patterns were correlated with clinicopathological parameters, overall survival (OS), and recurrence-free interval (RFI). Cases with high nuclear RBM3 protein expression had a prolonged 5-year OS in both cohorts when analyzing adenocarcinomas separately (P = .02 and P = .01). RBM3 remained an independent prognostic factor for OS in multivariable analysis of cohort I (HR 0.44, 95% CI 0.21-0.90) and for RFI in cohort II (HR 0.38, 95% CI 0.22-0.74). In squamous cell carcinoma, there was instead an insignificant association to poor prognosis. Also, the expression levels of RBM3 mRNA were investigated in 2087 lung adenocarcinomas and 899 squamous cell carcinomas assembled from 13 and 8 public gene expression microarray datasets, respectively. The RBM3 mRNA levels were not clearly associated with patient outcome in either adenocarcinomas or squamous cell carcinomas. Conclusions The results from this study support that high protein expression of RBM3 is linked to improved outcome in lung adenocarcinoma., QC 20201214

Published
2020
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17. Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author

Ward, H.A. Whitman, J. Muller, D.C. Johansson, M. Jakszyn, P. Weiderpass, E. Palli, D. Fanidi, A. Vermeulen, R. Tjønneland, A. Hansen, L. Dahm, C.C. Overvad, K. Severi, G. Boutron-Ruault, M.-C. Affret, A. Kaaks, R. Fortner, R. Boeing, H. Trichopoulou, A. La Vecchia, C. Kotanidou, A. Berrino, F. Krogh, V. Tumino, R. Ricceri, F. Panico, S. Bueno-de-Mesquita, H.B. Peeters, P.H. Nøst, T.H. Sandanger, T.M. Quirós, J.R. Agudo, A. Rodríguez-Barranco, M. Larrañaga, N. Huerta, J.M. Ardanaz, E. Drake, I. Brunnström, H. Johansson, M. Grankvist, K. Travis, R.C. Freisling, H. Stepien, M. Merritt, M.A. Riboli, E. Cross, A.J.

Abstract

Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00–1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02–1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case–control subset. Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk. © 2018, Springer Nature Limited.

Published
2019

18. Erratum: Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature communications (2019) 10 1 (431))

Author

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

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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2019
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19. Shared heritability and functional enrichment across six solid cancers.

Author

Jiang, X, Finucane, Hk, Schumacher, Fr, Schmit, Sl, Tyrer, Jp, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, Kb, Dennis, J, Conti, Dv, Casey, G, Gaudet, Mm, Huyghe, Jr, Albanes, D, Aldrich, Mc, Andrew, A, Andrulis, Il, Anton-Culver, H, Antoniou, Ac, Antonenkova, Nn, Arnold, Sm, Aronson, Kj, Arun, Bk, Bandera, Ev, Barkardottir, Rb, Barnes, Dr, Batra, J, Beckmann, Mw, Benitez, J, Benlloch, S, Berchuck, A, Berndt, Si, Bickeböller, H, Bien, Sa, Blomqvist, C, Boccia, Stefania, Bogdanova, Nv, Bojesen, Se, Bolla, Mk, Brauch, H, Brenner, H, Brenton, Jd, Brook, Mn, Brunet, J, Brunnström, H, Buchanan, Dd, Burwinkel, B, Butzow, R, Cadoni, Gabriella, Caldés, T, Caligo, Ma, Campbell, I, Campbell, Pt, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, Al, Chan, At, Chang-Claude, J, Chanock, Sj, Chen, C, Christiani, Dc, Claes, Kbm, Claessens, F, Clements, J, Collée, Jm, Correa, Mc, Couch, Fj, Cox, A, Cunningham, Jm, Cybulski, C, Czene, K, Daly, Mb, Defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, Jl, Dörk, T, Duell, Ej, Dunning, Am, Dwek, M, Eccles, Dm, Edlund, Ck, Edwards, Drv, Ellberg, C, Evans, Dg, Fasching, Pa, Ferris, Rl, Liloglou, T, Figueiredo, Jc, Fletcher, O, Fortner, Rt, Fostira, F, Franceschi, S, Friedman, E, Gallinger, Sj, Ganz, Pa, Garber, J, García-Sáenz, Ja, Gayther, Sa, Giles, Gg, Godwin, Ak, Goldberg, M, Goldgar, De, Goode, El, Goodman, Mt, Goodman, G, Grankvist, K, Greene, Mh, Gronberg, H, Gronwald, J, Guénel, P, Håkansson, N, Hall, P, Hamann, U, Hamdy, Fc, Hamilton, Rj, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Høgdall, E, Hong, Yc, Hopper, Jl, Houlston, R, Hulick, Pj, Hunter, Dj, Huntsman, Dg, Idos, G, Imyanitov, En, Ingles, Sa, Isaacs, C, Jakubowska, A, James, P, Jenkins, Ma, Johansson, M, John, Em, Joshi, Ad, Kaneva, R, Karlan, By, Kelemen, Le, Kühl, T, Khaw, Kt, Khusnutdinova, E, Kibel, A, Kiemeney, La, Kim, J, Kjaer, Sk, Knight, Ja, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, Vn, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, Mt, Lazarus, P, Le, Nd, Lee, E, Lejbkowicz, F, Lenz, Hj, Leslie, G, Lessel, D, Lester, J, Levine, Da, Li, L, Li, Ci, Lindblom, A, Lindor, Nm, Liu, G, Loupakis, F, Lubiński, J, Maehle, L, Maier, C, Mannermaa, A, Marchand, Ll, Margolin, S, May, T, Mcguffog, L, Meindl, A, Middha, P, Miller, A, Milne, Rl, Macinnis, Rj, Modugno, F, Montagna, M, Moreno, V, Moysich, Kb, Mucci, L, Muir, K, Mulligan, Am, Nathanson, Kl, Neal, De, Ness, Ar, Neuhausen, Sl, Nevanlinna, H, Newcomb, Pa, Newcomb, Lf, Nielsen, Fc, Nikitina-Zake, L, Nordestgaard, Bg, Nussbaum, Rl, Offit, K, Olah, E, Olama, Aaa, Olopade, Oi, Olshan, Af, Olsson, H, Osorio, A, Pandha, H, Park, Jy, Pashayan, N, Parsons, Mt, Pejovic, T, Penney, Kl, Peters, Whm, Phelan, Cm, Phipps, Ai, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, Sj, Raskin, L, Rennert, G, Rennert, H, van Rensburg, Ej, Riggan, Mj, Risch, Ha, Risch, A, Roobol, Mj, Rosenstein, B, Rossing, Ma, De Ruyck, K, Saloustros, E, Sandler, Dp, Sawyer, Ej, Schabath, Mb, Schleutker, J, Schmidt, Mk, Setiawan, Vw, Shen, H, Siegel, Em, Sieh, W, Singer, Cf, Slattery, Ml, Sorensen, Kd, Southey, Mc, Spurdle, Ab, Stanford, Jl, Stevens, Vl, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, Aj, Tajara, Eh, Tangen, Cm, Tardon, A, Taylor, Ja, Teare, Md, Teixeira, Mr, Terry, Mb, Terry, Kl, Thibodeau, Sn, Thomassen, M, Bjørge, L, Tischkowitz, M, Toland, Ae, Torres, D, Townsend, Pa, Travis, Rc, Tung, N, Tworoger, S, Ulrich, Cm, Usmani, N, Vachon, Cm, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, Me, Wang, Q, Webb, Pm, Weinberg, Cr, Weinstein, S, Weissler, Mc, Weitzel, Jn, West, Cml, White, E, Whittemore, A, Wichmann, He, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, Ah, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, Kk, Lane, Jm, Saxena, R, Thomas, D, Hung, Rj, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, García-Closas, M, Eeles, Ra, Chenevix-Trench, G, Brennan, Pj, Haiman, Ca, Simard, J, Easton, Df, Gruber, Sb, Pharoah, Pdp, Price, Al, Pasaniuc, B, Amos, Ci, Kraft, P, Lindström, S., Boccia S (ORCID:0000-0002-1864-749X), Cadoni G (ORCID:0000-0001-8244-784X), Jiang, X, Finucane, Hk, Schumacher, Fr, Schmit, Sl, Tyrer, Jp, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, Kb, Dennis, J, Conti, Dv, Casey, G, Gaudet, Mm, Huyghe, Jr, Albanes, D, Aldrich, Mc, Andrew, A, Andrulis, Il, Anton-Culver, H, Antoniou, Ac, Antonenkova, Nn, Arnold, Sm, Aronson, Kj, Arun, Bk, Bandera, Ev, Barkardottir, Rb, Barnes, Dr, Batra, J, Beckmann, Mw, Benitez, J, Benlloch, S, Berchuck, A, Berndt, Si, Bickeböller, H, Bien, Sa, Blomqvist, C, Boccia, Stefania, Bogdanova, Nv, Bojesen, Se, Bolla, Mk, Brauch, H, Brenner, H, Brenton, Jd, Brook, Mn, Brunet, J, Brunnström, H, Buchanan, Dd, Burwinkel, B, Butzow, R, Cadoni, Gabriella, Caldés, T, Caligo, Ma, Campbell, I, Campbell, Pt, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, Al, Chan, At, Chang-Claude, J, Chanock, Sj, Chen, C, Christiani, Dc, Claes, Kbm, Claessens, F, Clements, J, Collée, Jm, Correa, Mc, Couch, Fj, Cox, A, Cunningham, Jm, Cybulski, C, Czene, K, Daly, Mb, Defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, Jl, Dörk, T, Duell, Ej, Dunning, Am, Dwek, M, Eccles, Dm, Edlund, Ck, Edwards, Drv, Ellberg, C, Evans, Dg, Fasching, Pa, Ferris, Rl, Liloglou, T, Figueiredo, Jc, Fletcher, O, Fortner, Rt, Fostira, F, Franceschi, S, Friedman, E, Gallinger, Sj, Ganz, Pa, Garber, J, García-Sáenz, Ja, Gayther, Sa, Giles, Gg, Godwin, Ak, Goldberg, M, Goldgar, De, Goode, El, Goodman, Mt, Goodman, G, Grankvist, K, Greene, Mh, Gronberg, H, Gronwald, J, Guénel, P, Håkansson, N, Hall, P, Hamann, U, Hamdy, Fc, Hamilton, Rj, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Høgdall, E, Hong, Yc, Hopper, Jl, Houlston, R, Hulick, Pj, Hunter, Dj, Huntsman, Dg, Idos, G, Imyanitov, En, Ingles, Sa, Isaacs, C, Jakubowska, A, James, P, Jenkins, Ma, Johansson, M, John, Em, Joshi, Ad, Kaneva, R, Karlan, By, Kelemen, Le, Kühl, T, Khaw, Kt, Khusnutdinova, E, Kibel, A, Kiemeney, La, Kim, J, Kjaer, Sk, Knight, Ja, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, Vn, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, Mt, Lazarus, P, Le, Nd, Lee, E, Lejbkowicz, F, Lenz, Hj, Leslie, G, Lessel, D, Lester, J, Levine, Da, Li, L, Li, Ci, Lindblom, A, Lindor, Nm, Liu, G, Loupakis, F, Lubiński, J, Maehle, L, Maier, C, Mannermaa, A, Marchand, Ll, Margolin, S, May, T, Mcguffog, L, Meindl, A, Middha, P, Miller, A, Milne, Rl, Macinnis, Rj, Modugno, F, Montagna, M, Moreno, V, Moysich, Kb, Mucci, L, Muir, K, Mulligan, Am, Nathanson, Kl, Neal, De, Ness, Ar, Neuhausen, Sl, Nevanlinna, H, Newcomb, Pa, Newcomb, Lf, Nielsen, Fc, Nikitina-Zake, L, Nordestgaard, Bg, Nussbaum, Rl, Offit, K, Olah, E, Olama, Aaa, Olopade, Oi, Olshan, Af, Olsson, H, Osorio, A, Pandha, H, Park, Jy, Pashayan, N, Parsons, Mt, Pejovic, T, Penney, Kl, Peters, Whm, Phelan, Cm, Phipps, Ai, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, Sj, Raskin, L, Rennert, G, Rennert, H, van Rensburg, Ej, Riggan, Mj, Risch, Ha, Risch, A, Roobol, Mj, Rosenstein, B, Rossing, Ma, De Ruyck, K, Saloustros, E, Sandler, Dp, Sawyer, Ej, Schabath, Mb, Schleutker, J, Schmidt, Mk, Setiawan, Vw, Shen, H, Siegel, Em, Sieh, W, Singer, Cf, Slattery, Ml, Sorensen, Kd, Southey, Mc, Spurdle, Ab, Stanford, Jl, Stevens, Vl, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, Aj, Tajara, Eh, Tangen, Cm, Tardon, A, Taylor, Ja, Teare, Md, Teixeira, Mr, Terry, Mb, Terry, Kl, Thibodeau, Sn, Thomassen, M, Bjørge, L, Tischkowitz, M, Toland, Ae, Torres, D, Townsend, Pa, Travis, Rc, Tung, N, Tworoger, S, Ulrich, Cm, Usmani, N, Vachon, Cm, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, Me, Wang, Q, Webb, Pm, Weinberg, Cr, Weinstein, S, Weissler, Mc, Weitzel, Jn, West, Cml, White, E, Whittemore, A, Wichmann, He, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, Ah, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, Kk, Lane, Jm, Saxena, R, Thomas, D, Hung, Rj, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, García-Closas, M, Eeles, Ra, Chenevix-Trench, G, Brennan, Pj, Haiman, Ca, Simard, J, Easton, Df, Gruber, Sb, Pharoah, Pdp, Price, Al, Pasaniuc, B, Amos, Ci, Kraft, P, Lindström, S., Boccia S (ORCID:0000-0002-1864-749X), and Cadoni G (ORCID:0000-0001-8244-784X)

Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019

21. P1.14-37 Lung Cancer in Never-Smokers: A Nationwide Population Based Mapping of Targetable Alterations

Author

Salomonsson, A., primary, Jönsson, M., additional, Reuterswärd, C., additional, Behndig, A., additional, Bergman, B., additional, Botling, J., additional, Brandén, E., additional, Brunnström, H., additional, De Petris, L., additional, Hussein, A., additional, Johansson, M., additional, Koyi, H., additional, Lundström, K. Lamberg, additional, Lewensohn, R., additional, Monsef, N., additional, Ortiz-Villalón, C., additional, Patthey, A., additional, Vikström, A., additional, Wagenius, G., additional, Staaf, J., additional, and Planck, M., additional

Published
2019
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22. Synchrotron Phase Contrast Micro-CT as a Novel Tool for Understanding Pulmonary Vascular Pathobiology and the 3D Micro-Anatomy of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins

Author

Tran-Lundmark, K., primary, Westöö, C., additional, Norvik, C., additional, Peruzzi, N., additional, Lovric, G., additional, van der Have, O., additional, Mokso, R., additional, Jeremiasen, I., additional, Brunnström, H., additional, Galambos, C., additional, and Bech, M., additional

Published
2019
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23. A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer

Author

Salomonsson, A., Patthey, Annika, Reuterswärd, C., Jönsson, M., Botling, J., Brunnström, H., Hussein, A., Monsef, N., Ortiz-Villalon, C., Bergman, B., De Petris, L., Lamberg, K., Vikström, A., Wagenius, G., Behndig, Annelie F., Brandén, E., Johansson, Mikael, Koyi, H., Staaf, J., Planck, M., Salomonsson, A., Patthey, Annika, Reuterswärd, C., Jönsson, M., Botling, J., Brunnström, H., Hussein, A., Monsef, N., Ortiz-Villalon, C., Bergman, B., De Petris, L., Lamberg, K., Vikström, A., Wagenius, G., Behndig, Annelie F., Brandén, E., Johansson, Mikael, Koyi, H., Staaf, J., and Planck, M.

Abstract

Background: Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes. Method: Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients' medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4]. Result: In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented. Conclusion: SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.

Published
2018
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24. MA21.07 A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer

Author

Salomonsson, A., primary, Patthey, A., additional, Reuterswärd, C., additional, Jönsson, M., additional, Botling, J., additional, Brunnström, H., additional, Hussein, A., additional, Monsef, N., additional, Ortiz-Villalon, C., additional, Bergman, B., additional, De Petris, L., additional, Lamberg, K., additional, Vikström, A., additional, Wagenius, G., additional, Behndig, A., additional, Brandén, E., additional, Johansson, M., additional, Koyi, H., additional, Staaf, J., additional, and Planck, M., additional

Published
2018
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27. P2.02-015 Mutation Patterns in a Swedish Non-Small Cell Lung Cancer Cohort

Author

La Fleur, L., primary, Falk-Sörqvist, E., additional, Smeds, P., additional, Mattsson, J., additional, Sundström, M., additional, Branden, E., additional, Koyi, H., additional, Isaksson, J., additional, Brunnström, H., additional, Nilsson, M., additional, Micke, P., additional, Moens, L., additional, and Botling, J., additional

Published
2017
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28. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Author

McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., Amos, C.I., McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., and Amos, C.I.

Abstract

Contains fulltext : 177377.pdf (Publisher’s version ) (Closed access)

Published
2017

29. The accuracy of short clinical rating scales in neuropathologically diagnosed dementia.

Author

Gustafson, L, Englund, E, Brunnström, H, Brun, A, Erikson, C, Warkentin, Siegbert, Passant, U, Gustafson, L, Englund, E, Brunnström, H, Brun, A, Erikson, C, Warkentin, Siegbert, and Passant, U

Abstract

Objective: The overall aim was to evaluate to what extent the diagnosis of dementia subtypes, obtained by three clinical rating scales, concurred with postmortem neuropathologic (NP) diagnosis of Alzheimer disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD) and mixed AD/VaD. Design: A prospective longitudinal clinical work-up with postmortem NP examination. Participants: Two hundred nine patients with dementia referred for clinical evaluation and follow-up. Methods: The diagnostic scores in a set of three short clinical rating scales for AD, FTD, and VaD were evaluated against NP diagnoses. Results: The sensitivity and specificity of the AD scale were 0.80 and 0.87, respectively, of the FTD scale 0.93 and 0.92, respectively, and of the Hachinski Ischemic Score (HIS, VaD diagnosis) 0.69 and 0.92, respectively. Cases with mixed AD/VaD generally presented a combination of high AD and ischemic scores. A preferred cutoff score of six was identified for both the AD and FTD scales. Conclusions: All three clinical rating scales showed a high sensitivity and specificity, in close agreement with final NP diagnosis-for the HIS a moderate sensitivity. These scales may thus be considered good diagnostic tools and are recommended for clinical and research center settings.

Published
2010
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33. Clinicopathological concordance in dementia diagnostics.

Author

Brunnström H, Englund E, Brunnström, Hans, and Englund, Elisabet

Abstract

Objective: Accurate distinction between dementia subtypes is important for patient care and pharmacological treatment. Continuing systematic comparisons of clinical and neuropathological dementia diagnoses may provide a basis for further improvement of the diagnostic procedure. The purpose of this study was to investigate concordance between clinical dementia diagnosis and neuropathological findings in the specialized dementia care.Methods: Inclusion required 1) a clinical dementia disorder diagnosed at a hospital-based memory clinic and 2) a neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1996-2006. A total of 176 consecutive patients fulfilled the criteria and were thus included. Clinical dementia diagnoses were obtained from the medical records and compared with the neuropathological findings.Results: The clinical and pathological dementia diagnoses were in full accordance in 86 (49%) of the patients (kappa 0.37). In an additional 24 (14%) cases, the clinical diagnosis corresponded with some but not all pathological components judged to contribute to the dementia disorder. Of the patients with clinical Alzheimer disease, 84% (46/55) had a significant Alzheimer component with or without other significant pathology at neuropathological examination. The corresponding figure for vascular dementia (VaD) was 59% (24/41), for frontotemporal dementia 74% (20/27), for combined Alzheimer and VaD 25% (4/16), and for dementia with Lewy bodies 67% (6/9).Conclusions: This study shows that clinical dementia diagnoses do not always correspond with neuropathological changes. It stresses the importance of neuropathological examination in research and in daily clinical practice. [ABSTRACT FROM AUTHOR]

Published
2009
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34. Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer

Author

Max Backman, Carina Strell, Amanda Lindberg, Johanna S.M. Mattsson, Hedvig Elfving, Hans Brunnström, Aine O'Reilly, Martina Bosic, Miklos Gulyas, Johan Isaksson, Johan Botling, Klas Kärre, Karin Jirström, Kristina Lamberg, Fredrik Pontén, Karin Leandersson, Artur Mezheyeuski, Patrick Micke, Institut Català de la Salut, [Backman M, Lindberg A, Mattsson JSM, Elfving H] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [Strell C] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway. [Brunnström H] Division of Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. [Mezheyeuski A] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Immunologic Tests::Immunophenotyping [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Cancer Research, Tumour microenvironment, Cancer och onkologi, diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::pruebas inmunológicas::inmunofenotipificación [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Otros calificadores::/diagnóstico [Otros calificadores], Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES], Multiplex imaging, Checkpoint therapy, NSCLC, Cèl·lules T, Oncology, Immune cell infiltration, Cancer and Oncology, Pulmons - Càncer - Diagnòstic, Other subheadings::/diagnosis [Other subheadings], Lung cancer
Abstract

Checkpoint therapy; Lung cancer; Tumour microenvironment Terapia de puntos de control; Cáncer de pulmón; Microambiente tumoral Teràpia de punts de control; Càncer de pulmó; Microambient tumoral Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC). Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable. Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use. This study was partly supported by Swedish Cancer Society, The Lions Cancer Foundation Uppsala, Sweden, Selanders Foundation and The Sjöberg Foundation, Sweden.

Published
2023

35. Reference standards for gene fusion molecular assays on cytological samples: an international validation study

Author

Elena Vigliar, Eugenio Gautiero, Annalisa Altimari, Reinhard Büttner, Birgit Weynand, Carlos E. de Andrea, Philippe Vielh, Francesco Pepe, Claudio Bellevicine, Paul Hofman, Miguel Angel Molina Vila, Rossella Bruno, Fernando Schmitt, Véronique Hofman, Giancarlo Troncone, Francesc Tresserra, Luis Cirnes, Rafael Rosell, Ruth Román, Sabine Merkelbach-Bruse, David Gentien, Fabio Pagni, Dario de Biase, Catherine I. Dumur, Giulia Anna Carmen Vita, Kajsa Ericson Lindquist, Gabriella Fontanini, Sinchita Roy-Chowdhuri, Janna Siemanowski, Maria D. Lozano, Clara Mayo-de-las-Casas, Pasquale Pisapia, Sara Vander Borght, Antonino Iaccarino, Hans Brunnström, Umberto Malapelle, Giovanni Tallini, Malapelle, U, Pepe, F, Pisapia, P, Altimari, A, Bellevicine, C, Brunnström, H, Bruno, R, Büttner, R, Cirnes, L, De Andrea, C, de Biase, D, Dumur, C, Ericson Lindquist, K, Fontanini, G, Gautiero, E, Gentien, D, Hofman, P, Hofman, V, Iaccarino, A, Lozano, M, Mayo-de-Las-Casas, C, Merkelbach-Bruse, S, Pagni, F, Roman, R, Schmitt, F, Siemanowski, J, Roy-Chowdhuri, S, Tallini, G, Tresserra, F, Vander Borght, S, Vielh, P, Vigliar, E, Vita, G, Weynand, B, Rosell, R, Molina Vila, M, Troncone, G, Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Altimari, Annalisa, Bellevicine, Claudio, Brunnström, Han, Bruno, Rossella, Büttner, Reinhard, Cirnes, Lui, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Ericson Lindquist, Kajsa, Fontanini, Gabriella, Gautiero, Eugenio, Gentien, David, Hofman, Paul, Hofman, Veronique, Iaccarino, Antonino, Lozano, Maria Dolore, Mayo-de-Las-Casas, Clara, Merkelbach-Bruse, Sabine, Pagni, Fabio, Roman, Ruth, Schmitt, Fernando C, Siemanowski, Janna, Roy-Chowdhuri, Sinchita, Tallini, Giovanni, Tresserra, Francesc, Vander Borght, Sara, Vielh, Philippe, Vigliar, Elena, Vita, Giulia Anna Carmen, Weynand, Birgit, Rosell, Rafael, Molina Vila, Miguel Angel, and Troncone, Giancarlo

Subjects
Validation study, Staining and Labeling, Oncogene Proteins, Fusion, May-Grunwald giemsa, cytological techniques, molecular, molecular biology, pathology, Papanicolaou stain, General Medicine, Reference Standards, Amplicon, Biology, Molecular biology, Pathology and Forensic Medicine, Staining, Fusion gene, Cytological Techniques, Neoplasms, Humans, cytological technique, Reference standards
Abstract

AimsGene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated.MethodsCell lines harbouringEML4(13)–ALK(20) andSLC34A2(4)–ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides.ResultsFour (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms.ConclusionsReference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.

Published
2023

36. The prognostic value of programmed death-ligand 1 (PD-L1) expression in resected colorectal cancer without neoadjuvant therapy - differences between antibody clones and cell types.

Author

Nobin H, Garvin S, Hagman H, Nodin B, Jirström K, and Brunnström H

Subjects
Humans, Male, Female, Prognosis, Aged, Middle Aged, Retrospective Studies, Aged, 80 and over, Neoadjuvant Therapy methods, Antibodies, Monoclonal therapeutic use, Adult, Colorectal Neoplasms pathology, Colorectal Neoplasms surgery, Colorectal Neoplasms mortality, Colorectal Neoplasms metabolism, Colorectal Neoplasms immunology, B7-H1 Antigen metabolism, Biomarkers, Tumor metabolism
Abstract

Background: Programmed death-ligand 1 (PD-L1) expression on tumor cells is associated with poor prognosis in several malignancies, while partly contradictory and inconclusive results have been presented for colorectal cancer (CRC). This study aimed to evaluate PD-L1 as a prognostic biomarker in CRC by comparing three different antibody clones., Methods: Patients surgically treated for CRC between January 1st, 2007, and December 31st, 2015, in Kalmar County, Sweden, were retrospectively included. Tissue microarrays from 862 primary tumors without neoadjuvant treatment were assessed for immunohistochemical expression of PD-L1 in tumor cells (TC) and immune cells (IC) using clones 73-10, SP263, and 22C3. Cox regression proportional hazard models were used to estimate hazard ratios for overall survival (OS) and disease-free interval (DFI) in univariable and multivariable analyses, with 1% and 5% set as cut-offs for positive expression in TC and IC respectively., Results: PD-L1 expression in TC was found in 89 (10%) cases for clone 73-10, 76 (9%) for clone SP263, and 38 (4%) for clone 22C3, while the numbers for IC were 317 (37%) cases for clone 73-10, 264 (31%) for clone SP263, and 89 (10%) for clone 22C3. PD-L1 expression in IC was associated with prolonged OS and DFI in univariable analysis for all three clones. The link to prolonged DFI remained in multivariable analysis for 73-10 and SP263, but only for 73-10 regarding OS. PD-L1 expression in TC was not prognostic of OS in any analysis, while it was associated with prolonged DFI for SP263, and a trend was seen for 73-10. The link to prolonged DFI remained for SP263 and was strengthened for 73-10 in multivariable analysis., Conclusions: The prognostic value of PD-L1 expression in both IC and TC differs between antibody clones, with 73-10 and SP263 being more reliable for prognostic information than 22C3 in resected CRC., (© 2024. The Author(s).)

Published
2024
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37. Diagnostic gastrointestinal markers in primary lung cancer and pulmonary metastases.

Author

Malmros K, Lindholm A, Vidarsdottir H, Jirström K, Nodin B, Botling J, Mattsson JSM, Micke P, Planck M, Jönsson M, Staaf J, and Brunnström H

Subjects
Humans, Immunohistochemistry, Gastrointestinal Neoplasms pathology, Gastrointestinal Neoplasms diagnosis, Gastrointestinal Neoplasms metabolism, Diagnosis, Differential, Adenocarcinoma of Lung secondary, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung diagnosis, Adenocarcinoma of Lung metabolism, Tissue Array Analysis, Male, CDX2 Transcription Factor metabolism, CDX2 Transcription Factor analysis, Female, Cadherins metabolism, Cadherins analysis, Aged, Biomarkers, Tumor analysis, Lung Neoplasms pathology, Lung Neoplasms secondary, Lung Neoplasms metabolism, Lung Neoplasms diagnosis, Adenocarcinoma secondary, Adenocarcinoma diagnosis, Adenocarcinoma pathology, Adenocarcinoma metabolism
Abstract

Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25-50% and 5-16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer., (© 2023. The Author(s).)

Published
2024
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38. The impact of different fixatives on immunostaining of lung adenocarcinomas in pleural effusion cell blocks.

Author

Mansour MSI, Pettersson L, Seidal T, Strömberg U, Mager U, Ali L, Kumbaric S, Hejny K, Taheri-Eilagh F, Mufti J, Nakdali D, and Brunnström H

Abstract

Background: Cell blocks (CBs) are widely used for biomarker analyses such as immunostaining. Although immunohistochemistry on formalin-fixed paraffin-embedded tissues is standardized, there are multiple preparation methods and fixatives for cytology. Our objective was to investigate the effect of different common fixatives on the immunoreactivity of pleural effusion CBs with metastatic lung adenocarcinomas., Methods: This prospective study included 24 malignant pleural effusions from different patients with lung adenocarcinoma. From each case, four identical CBs were fixed in 10% neutral buffered formalin, PreservCyt, CytoLyt, and CytoRich Red (only 17 of the cases), respectively. Samples containing <100 malignant cells were excluded. All CBs were stained with thyroid transcription factor 1 (TTF-1; clones 8G7G3/1 and SPT24), napsin A, claudin 4, CEA, CK7, and epithelial cell adhesion molecule (EpCAM; clones BS14, Ber-Ep4, and MOC-31). The fraction and intensity of stained cells were evaluated., Results: Of the investigated markers, a significant difference in staining proportion was seen for TTF-1 clone 8G7G3/1 and EpCAM clone MOC-31, especially with cases being negative in CytoLyt (33.3% and 83.3% positive, respectively) and PreservCyt (62.5% and 83.3%) whereas being positive in CytoRich Red (76.5% and 94.1%) and formalin (both 95.8%). A significantly weaker intensity of staining was seen for all alcohol-based fixatives compared to formalin for TTF-1 clone 8G7G3/1, napsin A, and EpCAM clone MOC-31, whereas EpCAM clone Ber-Ep4 was significantly weaker only in PreservCyt compared with formalin., Conclusions: Immunocytochemical expression and concordance with formalin-fixed CBs differ depending on the used fixative as well as the antibody and clone, warranting investigation of the reliability of each biomarker for non-formalin-fixed cytology., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Published
2024
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39. First-line Treatment Patterns and Outcomes in Advanced Non-Small Cell Lung Cancer in Sweden: A Population-based Real-world Study with Focus on Immunotherapy.

Author

Wagenius G, Vikström A, Berglund A, Salomonsson S, Bencina G, Hu X, Chirovsky D, and Brunnström H

Subjects
Humans, B7-H1 Antigen metabolism, Sweden epidemiology, Immunotherapy, Retrospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms drug therapy, Lung Neoplasms metabolism
Abstract

Background and Purpose: The treatment landscape for patients with advanced non-small cell lung cancer (NSCLC) has evolved significantly since the introduction of immunotherapies. We here describe PD-L1 testing rates, treatment patterns, and real-world outcomes for PD-(L)1 inhibitors in Sweden., Materials and Methods: Data were obtained from the Swedish National Lung Cancer Registry for patients with advanced NSCLC and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 who initiated first-line -systemic treatment from 01 April 2017 to 30 June 2020. PD-L1 testing was available in the registry from 01 January 2018. Kaplan-Meier was used for overall survival (OS) by type treatment and histology., Results: A total of 2,204 patients with pathologically confirmed unresectable stage IIIB/C or IV NSCLC initiated first-line treatment, 1,807 (82%) with nonsquamous (NSQ) and 397 (18%) with SQ. Eighty-six per cent (NSQ) or 85% (SQ) had been tested for PD-L1 expression, a proportion that increased over time. The use of platinum-based therapy as first-line treatment decreased substantially over time while there was an upward trend for PD-(L)1-based therapy. Among patients with PS 0-1 initiating a first-line PD-(L)1 inhibitor monotherapy, the median OS was 18.6 and 13.3 months for NSQ and SQ NSCLC patients, respectively, while for the PD-(L)1 inhibitor and chemotherapy combination regimen, the median OS was 24.0 months for NSQ and not evaluable for SQ patients., Interpretation: The majority of advanced NSCLCs in Sweden were tested for PD-L1 expression. Real-world OS in patients with PS 0-1 receiving first-line PD-(L)1 inhibitor-based regimens was similar to what has been reported in pivotal clinical trials on PD-(L)1 inhibitors.

Published
2024
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40. Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma.

Author

Enokido T, Horie M, Yoshino S, Suzuki HI, Matsuki R, Brunnström H, Micke P, Nagase T, Saito A, and Miyashita N

Subjects
Humans, Cell Line, Tumor, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Butyrate Response Factor 1 genetics, Butyrate Response Factor 1 metabolism, Adenocarcinoma of Lung metabolism, MicroRNAs genetics, MicroRNAs metabolism, Small Cell Lung Carcinoma genetics, Lung Neoplasms pathology
Abstract

Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17∼92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17∼92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124-3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs., Implications: Our study revealed unique miRNA profiles of ASCL1-positive LUADs and identified ASCL1-regulated miRNAs with functional relevance., (©2023 American Association for Cancer Research.)

Published
2024
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41. Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer.

Author

Hikmet F, Rassy M, Backman M, Méar L, Mattsson JSM, Djureinovic D, Botling J, Brunnström H, Micke P, and Lindskog C

Subjects
Male, Humans, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Testis metabolism, Testis pathology, Neoplasm Proteins metabolism, Tumor Microenvironment, Transketolase metabolism, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms metabolism
Abstract

The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2023
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42. Real-world analysis of MET exon 14 mutations in non-small cell lung cancer: a retrospective study from two Swedish hospitals.

Author

Skribek M, Brunnström H, Oskarsdottir G, Portu Grivé M, Aricak O, Planck M, Jatta K, Naserhojati H, Haglund de Flon F, and Ekman S

Subjects
Humans, Exons genetics, Hospitals, University, Mutation, Retrospective Studies, Sweden epidemiology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
Abstract

Background: Real-World evidence on mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in lung cancer remains limited. With an incidence of 3-4% across histological subtypes, METex14 is now an actionable target for MET inhibitors (METi) in advanced lung cancer, demonstrating response rates between 30-70%. Yet, its role in early stages and sensitivity to immune checkpoint inhibitors (ICIs) is still under exploration., Material and Methods: We conducted a retrospective analysis of the clinical data of lung cancer patients presenting with METex14 across all stages. These patients were treated at two Swedish University Hospitals: Karolinska and Skåne, between the years 2014 and 2022., Results: We identified a total of 63 patients, of which 50 met the inclusion criteria. The median overall survival (OS) with corresponding 95% confidence intervals (95% CI) according to the stage was not reached (NR) for stage I, NR for stage II, 15 months (95% CI, 5.4-24.6) for stage III, and 17 months (95% CI, 9.2-NR) for stage IV. The median OS for stage IV patients who received a METi was 17 months (95% CI, 9.5-NR) vs. 10 months (95% CI, 6.2-NR) in patients without METi ( p  = 0.92; Hazard Ratio [HR] = 1.07). The median OS for stage IV patients who received ICIs was 18 months (95% CI, 16.5-NR) vs. 6 months (95% CI, 2.5-NR) in patients without ICIs ( p  = 0.15; HR = 0.47). The median OS for stage IV patients who received chemotherapy was 17 months (95% CI, 9.7-NR) vs. 10 months (95% CI, 4.5-NR) in patients without ( p  = 0.97; HR = 0.98)., Conclusions: Our data suggest limited survival benefits from METi, ICIs, and chemotherapy for METex14 lung cancer patients. While not statistically significant, these findings underscore the need for larger trials for validation. Identifying effective treatments for this challenging lung cancer subtype remains a priority.

Published
2023
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43. Comparison of immunohistochemical mesothelial biomarkers in paired biopsies and effusion cytology cell blocks from pleural mesothelioma.

Author

Mansour MSI, Huseinzade A, Seidal T, Hejny K, Maty A, Taheri-Eilagh F, Mager U, Dejmek A, Dobra K, and Brunnström H

Subjects
Humans, Calbindin 2, Tumor Suppressor Proteins metabolism, Biomarkers, Tumor analysis, Immunohistochemistry, Biopsy, Diagnosis, Differential, Lung Neoplasms diagnosis, Lung Neoplasms pathology, Mesothelioma, Malignant, Mesothelioma diagnosis, Mesothelioma pathology, Pleural Neoplasms diagnosis, Pleural Neoplasms pathology, Pleural Effusion diagnosis, Sarcoma diagnosis
Abstract

Objective: Traditionally, the diagnosis of pleural mesothelioma is based on histological material. Minimally invasive effusion cytology specimens are an alternative that, like biopsies, require ancillary analyses. Validation of immunohistochemical (IHC) analyses on cytology, including the surrogate markers for molecular alterations BAP1 and MTAP, is of interest., Methods: IHC for eight different markers was performed on 59 paired formalin-fixed, paraffin-embedded pleural biopsies and pleural effusion cell blocks with mesothelioma. Immunoreactivity in ≥10% of tumour cells was considered positive/preserved. The concordance between histological and cytological materials was assessed., Results: The overall percentage of agreement between the histological epithelioid component in 58 biopsies and paired cell blocks was 93% for calretinin, 98% for CK5, 97% for podoplanin, 90% for WT1, 86% for EMA, 100% for desmin, 91% for BAP1, and 72% for MTAP. For 11 cases with biphasic or sarcomatoid histology, the concordance between cytology and the histological sarcomatoid component was low for calretinin, CK5, and WT1 (all ≤45%). For the whole cohort, loss of both BAP1 and MTAP was seen in 40% while both markers were preserved in 11% of the biopsies for epithelioid histology. The corresponding numbers were 54% and 8%, respectively, for the paired cell blocks., Conclusions: Generally, a high concordance for IHC staining was seen between paired biopsies and pleural effusion cell blocks from mesotheliomas, but the somewhat lower agreement for WT1, EMA, and especially MTAP calls for further investigation and local quality assurance. The lower concordance for the sarcomatoid subtype for some markers may indicate biological differences., (© 2023 The Authors. Cytopathology published by John Wiley & Sons Ltd.)

Published
2023
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44. Treatment refractory arthritis and stroke - A case of infective endocarditis caused by Tropheryma whipplei .

Author

Ujaimi Z, Bjursten H, Vucicevic S, Brunnström H, Gilje P, Rasmussen M, and Ragnarsson S

Abstract

Whipple´s disease is a rare multisystem condition affecting < 1/1.000.000 per year. The condition often presents with polyarthritis, diarrhea, and intestinal malabsorption. Endocarditis is seen in a minority of these patients, and is typically culture negative, as the causative agent Tropheryma whipplei does not grow in ordinary culture media. We present the case of a 78-year-old man with a history of seronegative polyarthritis that was refractory to treatment with several biological agents for a duration of 5 years prior to presentation to the emergency department with stroke. Echocardiography revealed aortic valve endocarditis with a 3.6 cm vegetation and multiple smaller vegetations. The patient underwent surgery with aortic valve replacement followed by prolonged antibiotic treatment. 16 S rDNA PCR analysis of the resected valve revealed T. whipplei as the causative agent. Two years after surgery and treatment with antibiotics, the patient's previously longstanding arthritis had totally disappeared and all rheumatological treatment had been discontinued., Competing Interests: The authors have no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

Published
2023
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45. Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer.

Author

Backman M, Strell C, Lindberg A, Mattsson JSM, Elfving H, Brunnström H, O'Reilly A, Bosic M, Gulyas M, Isaksson J, Botling J, Kärre K, Jirström K, Lamberg K, Pontén F, Leandersson K, Mezheyeuski A, and Micke P

Subjects
Humans, Immunophenotyping, Tumor Microenvironment, CD8-Positive T-Lymphocytes, Prognosis, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
Abstract

Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC)., Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs)., Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable., Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.L. is a board member of Cantargia AB, a company developing IL1RAP inhibitors. This does not alter the author's adherence to all guidelines for publication and does not present a conflict of interest. All authors otherwise declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2023
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46. Pulmonary 5-HT 2B receptor expression in fibrotic interstitial lung diseases.

Author

Löfdahl A, Nybom A, Wigén J, Dellgren G, Brunnström H, Wenglén C, and Westergren-Thorsson G

Subjects
Humans, Serotonin, Endothelial Cells metabolism, Lung metabolism, Fibrosis, Lung Diseases, Interstitial metabolism, Lung Diseases, Interstitial pathology, Idiopathic Pulmonary Fibrosis pathology, Scleroderma, Systemic pathology
Abstract

Pulmonary fibrosis is a severe condition in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD, where the underlying mechanism is not well defined and with no curative treatments available. Serotonin (5-HT) signaling via the 5-HT 2B receptor has been recognized as a promising preclinical target for fibrosis. Despite this, the involvement of the 5-HT 2B receptor in fibrotic ILD is widely unexplored. This work highlights the spatial pulmonary distribution of the 5-HT 2B receptor in patients with IPF and systemic sclerosis-ILD. We show that the 5-HT 2B receptor is located in typical pathological structures e.g. honeycomb cysts and weakly in fibroblast foci. Together with immunohistochemistry and immunofluorescence stainings of patient derived distal lung tissues, we identified cell targets for 5-HT 2B receptor interference in type II alveolar epithelial cells, endothelial cells and M2 macrophages. Our results emphasize the role of 5-HT 2B receptor as a target in lung fibrosis, warranting further consideration in targeting fibrotic ILDs., Competing Interests: Conflict of interest The authors declare no conflict of interest, except C.W. that declare employment by AnaMar AB, a company developing 5-HT(2B) receptor antagonists for therapeutic purposes(.), (Copyright © 2023. Published by Elsevier GmbH.)

Published
2023
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47. Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension.

Author

van der Have O, Mead TJ, Westöö C, Peruzzi N, Mutgan AC, Norvik C, Bech M, Struglics A, Hoetzenecker K, Brunnström H, Westergren-Thorsson G, Kwapiszewska G, Apte SS, and Tran-Lundmark K

Abstract

Expansion of extracellular matrix occurs in all stages of pulmonary angiopathy associated with pulmonary arterial hypertension (PAH). In systemic arteries, dysregulation and accumulation of the large chondroitin-sulfate proteoglycan aggrecan is associated with swelling and disruption of vessel wall homeostasis. Whether aggrecan is present in pulmonary arteries, and its potential roles in PAH, has not been thoroughly investigated. Here, lung tissue from 11 patients with idiopathic PAH was imaged using synchrotron radiation phase-contrast microcomputed tomography (TOMCAT beamline, Swiss Light Source). Immunohistochemistry for aggrecan core protein in subsequently sectioned lung tissue demonstrated accumulation in PAH compared with failed donor lung controls. RNAscope in situ hybridization indicated ACAN expression in vascular endothelium and smooth muscle cells. Based on qualitative histological analysis, aggrecan localizes to cellular, rather than fibrotic or collagenous, lesions. Interestingly, ADAMTS15 , a potential aggrecanase, was upregulated in pulmonary arteries in PAH. Aligning traditional histological analysis with three-dimensional renderings of pulmonary arteries from synchrotron imaging identified aggrecan in lumen-reducing lesions containing loose, cell-rich connective tissue, at sites of intrapulmonary bronchopulmonary shunting, and at sites of presumed elevated pulmonary blood pressure. Our findings suggest that ACAN expression may be an early response to injury in pulmonary angiopathy and supports recent work showing that dysregulation of aggrecan turnover is a hallmark of arterial adaptations to altered hemodynamics. Whether cause or effect, aggrecan and aggrecanase regulation in PAH are potential therapeutic targets., Competing Interests: The author declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Published
2023
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48. Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features.

Author

Pellinen T, Paavolainen L, Martín-Bernabé A, Papatella Araujo R, Strell C, Mezheyeuski A, Backman M, La Fleur L, Brück O, Sjölund J, Holmberg E, Välimäki K, Brunnström H, Botling J, Moreno-Ruiz P, Kallioniemi O, Micke P, and Östman A

Subjects
Humans, Receptor, Platelet-Derived Growth Factor beta analysis, Receptor, Platelet-Derived Growth Factor beta genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, Biomarkers, Tumor metabolism, Fibroblasts metabolism, Fibroblasts pathology, Mutation, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Cancer-Associated Fibroblasts metabolism
Abstract

Background: Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome., Methods: Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival., Results: Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors., Conclusions: Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry-based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets., (© The Author(s) 2022. Published by Oxford University Press.)

Published
2023
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49. Reference standards for gene fusion molecular assays on cytological samples: an international validation study.

Author

Malapelle U, Pepe F, Pisapia P, Altimari A, Bellevicine C, Brunnström H, Bruno R, Büttner R, Cirnes L, De Andrea CE, de Biase D, Dumur CI, Ericson Lindquist K, Fontanini G, Gautiero E, Gentien D, Hofman P, Hofman V, Iaccarino A, Lozano MD, Mayo-de-Las-Casas C, Merkelbach-Bruse S, Pagni F, Roman R, Schmitt FC, Siemanowski J, Roy-Chowdhuri S, Tallini G, Tresserra F, Vander Borght S, Vielh P, Vigliar E, Vita GAC, Weynand B, Rosell R, Molina Vila MA, and Troncone G

Subjects
Humans, Reference Standards, Staining and Labeling, Neoplasms, Oncogene Proteins, Fusion
Abstract

Aims: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated., Methods: Cell lines harbouring EML4 (13) -ALK (20) and SLC34A2 (4) -ROS1 (32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides., Results: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms., Conclusions: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches., Competing Interests: Competing interests: UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck and Astra Zeneca, unrelated to the current work. Lukas Bubendorf has a consulting or advisory role with Astra Zeneca, AbbVie, Bayer, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Takeda and F. Hoffmann-La Roche and has received research funding (institution) from F. Hoffmann-La Roche, MSD and Sanofi. PH reports personal fees (as advisor) from Roche, Astrazeneca, BMS, MSD, Pfizer, Bayer, Amgen, Illumina, Qiagen, Thermo Fisher Scientific, Biocartis, Ed Lilly, unrelated to the current work. SM-B has received personal fees (as consultant and/or speaker bureau) from Astra Zeneca, Roche, BMS, Novartis, GSK, MSD, Targos, Merck, unrelated to the current work. Spasenija Savic Prince received personal fees from MSD, Astra Zeneca, Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb and Thermo Fisher Scientific, unrelated to the submitted work. EV has received personal fees (as consultant and/or speaker bureau) from Diaceutics, unrelated to the current work. GTr reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer, Boehringer Ingelheim, Eli Lilly, BMS, GSK, Menarini, AstraZeneca, Amgen and Bayer, unrelated to the current work. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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50. Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas.

Author

Thurfjell V, Micke P, Yu H, Krupar R, Svensson MA, Brunnström H, Lamberg K, Moens LNJ, Strell C, Gulyas M, Helenius G, Yoshida A, Goldmann T, and Mattsson JSM

Abstract

Background: Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts., Methods: Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays [all n=676, adenocarcinomas (AC) n=401, squamous cell carcinomas (SCC) n=213, other NSCLC n=62]. ROS1-rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular; ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n=21)., Results: Using FISH, 2/630 (0.3% all NSCLC; 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24/665 (3.6% all NSCLC; 5.1% non-squamous NSCLC) cases with clone D4D6, in 18/639 (2.8% all NSCLC; 3.9% non-squamous NSCLC) cases with clone SP384, and in 1/593 (0.2% all NSCLC; 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19/369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA-sequencing data. Other cases with high protein/RNA-expression or ambiguous FISH were negative in the NanoString-assay., Conclusions: The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-504/coif). VT reports support for study materials from the Lions Cancer Foundation, Uppsala, Sweden. PM reports support for the present manuscript from the Swedish Cancer Society, Vetenskapsrådet, Uppsala-Örebro Regional Research Council, and the Sjöberg Foundation. RK reports consulting fees from Aignostics GmbH. CS reports grants from the Swedish Cancer Society, Swedish Cancer Society Radiotherapy Fellowship, and Cancer- och Allergifonden Research. GH reports grants from Roche, honoraria from Bristol Meyer Squibb, payment for expert testimony from Astra Zeneca and Pfizer, and support for attending meetings and/or travel from Astra Zeneca. JSMM reports support for study materials from Selanders Stiftelse, Uppsala, Sweden, support for attending meetings from the Swedish Cancer Society, and receipt of materials from Zytomed Systems (anti-ROS1 mAb EPMGHR2). The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Published
2022
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