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144 results on '"Helland, Aslaug"'

5. Handling Missing MRI Input Data in Deep Learning Segmentation of Brain Metastases: A Multi-Center Study

Author

Grøvik, Endre, Yi, Darvin, Iv, Michael, Tong, Elizabeth, Nilsen, Line Brennhaug, Latysheva, Anna, Saxhaug, Cathrine, Jacobsen, Kari Dolven, Helland, Åslaug, Emblem, Kyrre Eeg, Rubin, Daniel, and Zaharchuk, Greg

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

The purpose was to assess the clinical value of a novel DropOut model for detecting and segmenting brain metastases, in which a neural network is trained on four distinct MRI sequences using an input dropout layer, thus simulating the scenario of missing MRI data by training on the full set and all possible subsets of the input data. This retrospective, multi-center study, evaluated 165 patients with brain metastases. A deep learning based segmentation model for automatic segmentation of brain metastases, named DropOut, was trained on multi-sequence MRI from 100 patients, and validated/tested on 10/55 patients. The segmentation results were compared with the performance of a state-of-the-art DeepLabV3 model. The MR sequences in the training set included pre- and post-gadolinium (Gd) T1-weighted 3D fast spin echo, post-Gd T1-weighted inversion recovery (IR) prepped fast spoiled gradient echo, and 3D fluid attenuated inversion recovery (FLAIR), whereas the test set did not include the IR prepped image-series. The ground truth were established by experienced neuroradiologists. The results were evaluated using precision, recall, Dice score, and receiver operating characteristics (ROC) curve statistics, while the Wilcoxon rank sum test was used to compare the performance of the two neural networks. The area under the ROC curve (AUC), averaged across all test cases, was 0.989+-0.029 for the DropOut model and 0.989+-0.023 for the DeepLabV3 model (p=0.62). The DropOut model showed a significantly higher Dice score compared to the DeepLabV3 model (0.795+-0.105 vs. 0.774+-0.104, p=0.017), and a significantly lower average false positive rate of 3.6/patient vs. 7.0/patient (p<0.001) using a 10mm3 lesion-size limit. The DropOut model may facilitate accurate detection and segmentation of brain metastases on a multi-center basis, even when the test cohort is missing MRI input data.

Published
2019

6. MRI Pulse Sequence Integration for Deep-Learning Based Brain Metastasis Segmentation

Author

Yi, Darvin, Grøvik, Endre, Iv, Michael, Tong, Elizabeth, Emblem, Kyrre Eeg, Nilsen, Line Brennhaug, Saxhaug, Cathrine, Latysheva, Anna, Jacobsen, Kari Dolven, Helland, Åslaug, Zaharchuk, Greg, and Rubin, Daniel

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Magnetic resonance (MR) imaging is an essential diagnostic tool in clinical medicine. Recently, a variety of deep learning methods have been applied to segmentation tasks in medical images, with promising results for computer-aided diagnosis. For MR images, effectively integrating different pulse sequences is important to optimize performance. However, the best way to integrate different pulse sequences remains unclear. In this study, we evaluate multiple architectural features and characterize their effects in the task of metastasis segmentation. Specifically, we consider (1) different pulse sequence integration schemas, (2) different modes of weight sharing for parallel network branches, and (3) a new approach for enabling robustness to missing pulse sequences. We find that levels of integration and modes of weight sharing that favor low variance work best in our regime of small data (n = 100). By adding an input-level dropout layer, we could preserve the overall performance of these networks while allowing for inference on inputs with missing pulse sequence. We illustrate not only the generalizability of the network but also the utility of this robustness when applying the trained model to data from a different center, which does not use the same pulse sequences. Finally, we apply network visualization methods to better understand which input features are most important for network performance. Together, these results provide a framework for building networks with enhanced robustness to missing data while maintaining comparable performance in medical imaging applications., Comment: In the IEEE transactions format for submission to IEEE-TMI

Published
2019

8. Rapid label expansion based on public-private collaboration in IMPRESS-Norway.

Author

Helland, Aslaug, primary, Tasken, Kjetil, additional, Blix, Egil Støre, additional, Lonning, Per Eystein, additional, Gjertsen, Bjorn T., additional, Hovland, Randi, additional, Randen, Ulla, additional, Gilje, Bjornar, additional, Kyte, Jon Amund, additional, Flobak, Åsmund, additional, Russnes, Hege, additional, Fagereng, Gro Live, additional, and Smeland, Sigbjørn, additional

Published
2024
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12. Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage–SCLC: Results From the Phase 3 MERU Study

Author

Johnson, Melissa L., Zvirbule, Zanete, Laktionov, Konstantin, Helland, Aslaug, Cho, Byoung Chul, Gutierrez, Vanesa, Colinet, Benoît, Lena, Herve, Wolf, Martin, Gottfried, Maya, Okamoto, Isamu, van der Leest, Cor, Rich, Patricia, Hung, Jen-Yu, Appenzeller, Christina, Sun, Zhaowen, Maag, David, Luo, Yan, Nickner, Caroline, Vajikova, Alena, Komarnitsky, Philip, and Bar, Jair

Published
2021
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14. Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects

Author

Zhang, Ruyang, Chen, Chao, Dong, Xuesi, Shen, Sipeng, Lai, Linjing, He, Jieyu, You, Dongfang, Lin, Lijuan, Zhu, Ying, Huang, Hui, Chen, Jiajin, Wei, Liangmin, Chen, Xin, Li, Yi, Guo, Yichen, Duan, Weiwei, Liu, Liya, Su, Li, Shafer, Andrea, Fleischer, Thomas, Moksnes Bjaanæs, Maria, Karlsson, Anna, Planck, Maria, Wang, Rui, Staaf, Johan, Helland, Åslaug, Esteller, Manel, Wei, Yongyue, Chen, Feng, and Christiani, David C.

Published
2020
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16. Increase in curative treatment and survival of lung cancer in Norway 2001–2016

Author

Solberg, Steinar, Nilssen, Yngvar, Brustugun, Odd Terje, Grimsrud, Tom Kristian, Haram, Per Magnus, Helbekkmo, Nina, Helland, Åslaug, Hjelde, Harald Harris, Jakobsen, Bjørn, Møller, Bjørn, Petersen, Martin, Strand, Trond-Eirik, Wahl, Sissel Gyrid Freim, Aanerud, Marianne, and Fjellbirkeland, Lars

Published
2019

17. Atezolizumab Treatment Beyond Progression in Advanced NSCLC: Results From the Randomized, Phase III OAK Study

Author

Gandara, David R., von Pawel, Joachim, Mazieres, Julien, Sullivan, Richard, Helland, Åslaug, Han, Ji-Youn, Ponce Aix, Santiago, Rittmeyer, Achim, Barlesi, Fabrice, Kubo, Toshio, Park, Keunchil, Goldschmidt, Jerome, Gandhi, Mayank, Yun, Cindy, Yu, Wei, Matheny, Christina, He, Pei, Sandler, Alan, Ballinger, Marcus, and Fehrenbacher, Louis

Published
2018
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19. Supplemental Table II from Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Author

Donnem, Tom, primary, Hald, Sigurd M., primary, Paulsen, Erna-Elise, primary, Richardsen, Elin, primary, Al-Saad, Samer, primary, Kilvaer, Thomas K., primary, Brustugun, Odd Terje, primary, Helland, Aslaug, primary, Lund-Iversen, Marius, primary, Poehl, Mette, primary, Olsen, Karen Ege, primary, Ditzel, Henrik J., primary, Hansen, Olfred, primary, Al-Shibli, Khalid, primary, Kiselev, Yury, primary, Sandanger, Torkjel M., primary, Andersen, Sigve, primary, Pezzella, Francesco, primary, Bremnes, Roy M., primary, and Busund, Lill-Tove, primary

Published
2023
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21. Prognostic Significance of the Loss of Heterozygosity of KRAS in Early-Stage Lung Adenocarcinoma

Author

Khadse, Anand, Haakensen, Vilde D., Silwal-Pandit, Laxmi, Hamfjord, Julian, Micke, Patrick, Botling, Johan, Brustugun, Odd Terje, Lingjaerde, Ole Christian, Helland, Aslaug, Kure, Elin H., Khadse, Anand, Haakensen, Vilde D., Silwal-Pandit, Laxmi, Hamfjord, Julian, Micke, Patrick, Botling, Johan, Brustugun, Odd Terje, Lingjaerde, Ole Christian, Helland, Aslaug, and Kure, Elin H.

Abstract

Lung cancer is a common disease with a poor prognosis. Genomic alterations involving the KRAS gene are common in lung carcinomas, although much is unknown about how different mutations, deletions, and expressions influence the disease course. The first approval of a KRAS-directed inhibitor was recently approved by the FDA. Mutations in the KRAS gene have been associated with poor prognosis for lung adenocarcinomas, but implications of the loss of heterozygosity (LOH) of KRAS have not been investigated. In this study, we have assessed the LOH of KRAS in early-stage lung adenocarcinoma by analyzing DNA copy number profiles and have investigated the effect on patient outcome in association with mRNA expression and somatic hotspot mutations. KRAS mutation was present in 36% of cases and was associated with elevated mRNA expression. LOH in KRAS was associated with a favorable prognosis, more prominently in KRAS mutated than in wild-type patients. The presence of both LOH and mutation in KRAS conferred a better prognosis than KRAS mutation alone. For wild-type tumors, no difference in prognosis was observed between patients with and without LOH in KRAS. Our study indicates that LOH in KRAS is an independent prognostic factor that may refine the existing prognostic groups of lung adenocarcinomas.

Published
2022
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23. Rovalpituzumab Tesirine as a Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage Small Cell Lung Cancer: Results From the Phase 3 MERU Study

Author

Johnson, Melissa L, Zvirbule, Zanete, Laktionov, Konstantin, Helland, Aslaug, Cho, Byoung Chul, Gutierrez, Vanesa, Colinet, Benoît, Lena, Herve, Wolf, Martin, Gottfried, Maya, Okamoto, Isamu, van der Leest, Cor, Rich, Patricia, Hung, Jen-Yu, Appenzeller, Christina, Sun, Zhaowen, Maag, David, Luo, Yan, Nickner, Caroline, Vajikova, Alena, Komarnitsky, Philip, Bar, Jair, Sarah Cannon Research Institute [Nashville, Tennessee], Riga East University Hospital, N.N. Blokhin Russian Cancer Research Center, Oslo University Hospital [Oslo], Yonsei University, Universidad de Málaga [Málaga] = University of Málaga [Málaga], Grand Hôpital de Charleroi [Belgium], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Kassel [Kassel], Meir Medical Center, Kyushu University, Amphia Ziekenhuis = Amphia Hospital [Breda, The Netherlands] (AZ=AH), Brustzentrum Kantonsspital St. Gallen, Abbvie Inc. [North Chicago], Kfar Saba and Sackler School of Medicine, AbbVie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kyushu University [Fukuoka], and Amphia Ziekenhuis

Subjects
Small cell lung cancer, Maintenance, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.CAN]Life Sciences [q-bio]/Cancer, DLL3, Phase 3, Rovalpituzumab tesirine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Platinum-based chemotherapy
Abstract

International audience; Introduction - Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy.Methods - MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors.Results - Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p

Published
2021

24. TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies

Author

Klug, Stefanie J, Ressing, Meike, Koenig, Jochem, Abba, Martin C, Agorastos, Theodoros, Brenna, Sylvia MF, Ciotti, Marco, Das, BR, Del Mistro, Annarosa, Dybikowska, Aleksandra, Giuliano, Anna R, Gudleviciene, Zivile, Gyllensten, Ulf, Haws, Andrea LF, Helland, Aslaug, Herrington, C Simon, Hildesheim, Alan, Humbey, Olivier, Jee, Sun H, Kim, Jae Weon, Madeleine, Margaret M, Menczer, Joseph, Ngan, Hextan YS, Nishikawa, Akira, Niwa, Yoshimitsu, Pegoraro, Rosemary, Pillai, MR, Ranzani, Gulielmina, Rezza, Giovanni, Rosenthal, Adam N, Roychoudhury, Susanta, Saranath, Dhananjaya, Schmitt, Virginia M, Sengupta, Sharmila, Settheetham-Ishida, Wannapa, Shirasawa, Hiroshi, Snijders, Peter JF, Stoler, Mark H, Suárez-Rincón, Angel E, Szarka, Krisztina, Tachezy, Ruth, Ueda, Masatsugu, van der Zee, Ate GJ, von Knebel Doeberitz, Magnus, Wu, Ming-Tsang, Yamashita, Tsuyoshi, Zehbe, Ingeborg, and Blettner, Maria

Published
2009
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27. Two truncating variants in FANCC and breast cancer risk

Author

Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Freeman, Laura E. Beane, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia, V, Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L., Chang-Claude, Jenny, Chanock, Stephen J., Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L., Couch, Fergus J., Czene, Kamila, Daly, Mary B., dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fritschisl, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., Garcia-Closas, Montserrat, Garcia-Saenz, Jose A., Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., Goldgar, David E., Guenel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Hakansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans B. L., Hooning, Maartje J., Hopper, John L., Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kwon, Ava, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindstrom, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, Meindl, Alfons, Menon, Usha, Milne, Roger L., Taib, Nur Aishah Mohd, Muir, Kenneth, Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Offit, Kenneth, Olopade, Olufunmilayo, I, Olshan, Andrew F., Olson, Janet E., Olsson, Hakan, Park, Sue K., Park-Simon, Tjoung-Won, Peto, Julian, Plaseska-Karanfilska, Dijana, Pohl-Rescigno, Esther, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Ruebner, Matthias, Saloustros, Emmanouil, Schmidt, Marjanka K., Schmutzler, Rita K., Schneider, Michael O., Schoemaker, Minouk J., Scott, Christopher, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Slager, Susan, Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teo, Soo H., Terry, Mary Beth, Toland, Amanda E., Tollenaar, Rob A. E. M., Torres, Diana, Torres-Mejia, Gabriela, Troester, Melissa A., Truong, Therese, Tsugane, Shoichiro, Untch, Michael, Vachon, Celine M., van den Ouweland, Ans M. W., van Veen, Elke M., Vijai, Joseph, Wendt, Camilla, Wolk, Alicja, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Ziv, Elad, Dunning, Alison M., Pharoah, Paul D. P., Schindler, Detlev, Devilee, Peter, Easton, Douglas F., Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Borresen-Dale, Anne-Lise, Alnaes, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Karesen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebraten, Olav, Naume, Bjorn, Fossa, Alexander, Kiserud, Cecile E., Reinertsen, Kristin, V, Helland, Aslaug, Riis, Margit, Geisler, Juergen, Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Freeman, Laura E. Beane, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia, V, Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L., Chang-Claude, Jenny, Chanock, Stephen J., Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L., Couch, Fergus J., Czene, Kamila, Daly, Mary B., dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fritschisl, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., Garcia-Closas, Montserrat, Garcia-Saenz, Jose A., Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., Goldgar, David E., Guenel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Hakansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans B. L., Hooning, Maartje J., Hopper, John L., Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kwon, Ava, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindstrom, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, Meindl, Alfons, Menon, Usha, Milne, Roger L., Taib, Nur Aishah Mohd, Muir, Kenneth, Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Offit, Kenneth, Olopade, Olufunmilayo, I, Olshan, Andrew F., Olson, Janet E., Olsson, Hakan, Park, Sue K., Park-Simon, Tjoung-Won, Peto, Julian, Plaseska-Karanfilska, Dijana, Pohl-Rescigno, Esther, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Ruebner, Matthias, Saloustros, Emmanouil, Schmidt, Marjanka K., Schmutzler, Rita K., Schneider, Michael O., Schoemaker, Minouk J., Scott, Christopher, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Slager, Susan, Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teo, Soo H., Terry, Mary Beth, Toland, Amanda E., Tollenaar, Rob A. E. M., Torres, Diana, Torres-Mejia, Gabriela, Troester, Melissa A., Truong, Therese, Tsugane, Shoichiro, Untch, Michael, Vachon, Celine M., van den Ouweland, Ans M. W., van Veen, Elke M., Vijai, Joseph, Wendt, Camilla, Wolk, Alicja, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Ziv, Elad, Dunning, Alison M., Pharoah, Paul D. P., Schindler, Detlev, Devilee, Peter, Easton, Douglas F., Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Borresen-Dale, Anne-Lise, Alnaes, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Karesen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebraten, Olav, Naume, Bjorn, Fossa, Alexander, Kiserud, Cecile E., Reinertsen, Kristin, V, Helland, Aslaug, Riis, Margit, and Geisler, Juergen

Abstract

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Published
2019
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28. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Author

Mavaddat, Nasim, Michailidou, Kyriaki, Dennis, Joe, Lush, Michael, Fachal, Laura, Lee, Andrew, Tyrer, Jonathan P., Chen, Ting-Huei, Wang, Qin, Bolla, Manjeet K., Yang, Xin, Adank, Muriel A., Ahearn, Thomas, Aittomaki, Kristiina, Allen, Jamie, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Auer, Paul L., Auvinen, Paivi, Barrdahl, Myrto, Freeman, Laura E. Beane, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia, V, Bojesen, Stig E., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Brenner, Hermann, Brentnall, Adam, Brock, Ian W., Brooks-Wilson, Angela, Brucker, Sara Y., Bruening, Thomas, Burwinkel, Barbara, Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chanock, Stephen J., Chlebowski, Rowan, Christiansen, Hans, Clarke, Christine L., Collee, J. Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Foersti, Asta, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M., Garcia-Saenz, Jose A., Gaudet, Mia M., Georgoulias, Vassilios, Giles, Graham G., Gilyazova, Irina R., Glendon, Gord, Goldberg, Mark S., Goldgar, David E., Gonzalez-Neira, Anna, Alnaes, Grethe I. Grenaker, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guenel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hankinson, Susan E., Harkness, Elaine F., Hart, Steven N., He, Wei, Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J., Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Johnson, Nichola, Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kaczmarek, Katarzyna, Kataja, Vesa, Keeman, Renske, Kerin, Michael J., Khusnutdinova, Elza, Kiiski, Johanna, I, Knight, Julia A., Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kristensen, Vessela N., Kruger, Ute, Kuehl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Lilyquist, Jenna, Lindblom, Annika, Lindstrom, Sara, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Long, Jirong, Lubinski, Jan, Lux, Michael P., MacInnis, Robert J., Maishman, Tom, Makalic, Enes, Kostovska, Ivana Maleva, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Menon, Usha, Middha, Pooja, Miller, Nicola, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Munoz-Garzon, Victor M., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Nielsen, Sune F., Nordestgaard, Borge G., Norman, Aaron, Offit, Kenneth, Olson, Janet E., Olsson, Hakan, Orr, Nick, Pankratz, V. Shane, Park-Simon, Tjoung-Won, Perez, Jose I. A., Perez-Barrios, Clara, Peterlongo, Paolo, Peto, Julian, Pinchev, Mila, Plaseska-Karanfilska, Dijana, Polley, Eric C., Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Purrington, Kristen, Pylkas, Katri, Rack, Brigitte, Radice, Paolo, Rau-Murthy, Rohini, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Robson, Mark, Romero, Atocha, Ruddy, Kathryn J., Ruebner, Matthias, Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schumacher, Fredrick, Schuermann, Peter, Schwentner, Lukas, Scott, Christopher, Scott, Rodney J., Seynaeve, Caroline, Shah, Mitul, Sherman, Mark E., Shrubsole, Martha J., Shu, Xiao-Ou, Slager, Susan, Smeets, Ann, Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Stegmaier, Christa, Stone, Jennifer, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Thoene, Kathrin, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Therese, Tzardi, Maria, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine M., van Veen, Elke M., Vijai, Joseph, Weinberg, Clarice R., Wendt, Camilla, Whittemore, Alice S., Wildiers, Hans, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Ziogas, Argyrios, Clarke, Christine, Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Sexton, Adrienne, Dobrovic, Alex, Christian, Alice, Trainer, Alison, Fellows, Andrew, Shelling, Andrew, De Fazio, Anna, Blackburn, Anneke, Crook, Ashley, Meiser, Bettina, Patterson, Briony, Clarke, Christobel, Saunders, Christobel, Hunt, Clare, Scott, Clare, Amor, David, Ortega, David Gallego, Marsh, Deb, Edkins, Edward, Salisbury, Elizabeth, Haan, Eric, Macrea, Finlay, Farshid, Gelareh, Lindeman, Geoff, Trench, Georgia, Mann, Graham, Giles, Graham, Gill, Grantley, Thorne, Heather, Campbell, Ian, Hickie, Ian, Caldon, Liz, Winship, Ingrid, Cui, James, Flanagan, James, Kollias, James, Visvader, Jane, Taylor, Jessica, Burke, Jo, Saunus, Jodi, Forbs, John, Hopper, John, Beesley, Jonathan, Kirk, Judy, French, Juliet, Tucker, Kathy, Wu, Kathy, Phillips, Kelly, Forrest, Laura, Lipton, Lara, Andrews, Leslie, Lobb, Lizz, Walker, Logan, Kentwell, Maira, Spurdle, Mandy, Cummings, Margaret, Gleeson, Margaret, Harris, Marion, Jenkins, Mark, Young, Mary Anne, Delatycki, Martin, Wallis, Mathew, Burgess, Matthew, Brown, Melissa, Southey, Melissa, Bogwitz, Michael, Field, Michael, Friedlander, Michael, Gattas, Michael, Saleh, Mona, Aghmesheh, Morteza, Hayward, Nick, Pachter, Nick, Cohen, Paul, Duijf, Pascal, James, Paul, Simpson, Pete, Fong, Peter, Butow, Phyllis, Williams, Rachael, Kefford, Rick, Simard, Jacques, Balleine, Rose-Mary, Dawson, Sarah-Jane, Lok, Sheau, O'connell, Shona, Greening, Sian, Nightingale, Sophie, Edwards, Stacey, Fox, Stephen, McLachlan, Sue-Anne, Lakhani, Sunil, Dudding, Tracy, Antill, Yoland, Sahlberg, Kristine K., Ottestad, Lars, Karesen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebraten, Olav, Naume, Bjorn, Fossa, Alexander, Kiserud, Cecile E., Reinertsen, Kristin, V, Helland, Aslaug, Riis, Margit, Geisler, Juergen, Dunning, Alison M., Thompson, Deborah J., Chenevix-Trench, Georgia, Chang-Claude, Jenny, Schmidt, Marjanka K., Hall, Per, Milne, Roger L., Pharoah, Paul D. P., Antoniou, Antonis C., Chatterjee, Nilanjan, Kraft, Peter, Garcia-Closas, Montserrat, Easton, Douglas F., Mavaddat, Nasim, Michailidou, Kyriaki, Dennis, Joe, Lush, Michael, Fachal, Laura, Lee, Andrew, Tyrer, Jonathan P., Chen, Ting-Huei, Wang, Qin, Bolla, Manjeet K., Yang, Xin, Adank, Muriel A., Ahearn, Thomas, Aittomaki, Kristiina, Allen, Jamie, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Auer, Paul L., Auvinen, Paivi, Barrdahl, Myrto, Freeman, Laura E. Beane, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia, V, Bojesen, Stig E., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Brenner, Hermann, Brentnall, Adam, Brock, Ian W., Brooks-Wilson, Angela, Brucker, Sara Y., Bruening, Thomas, Burwinkel, Barbara, Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chanock, Stephen J., Chlebowski, Rowan, Christiansen, Hans, Clarke, Christine L., Collee, J. Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Foersti, Asta, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M., Garcia-Saenz, Jose A., Gaudet, Mia M., Georgoulias, Vassilios, Giles, Graham G., Gilyazova, Irina R., Glendon, Gord, Goldberg, Mark S., Goldgar, David E., Gonzalez-Neira, Anna, Alnaes, Grethe I. Grenaker, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guenel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hankinson, Susan E., Harkness, Elaine F., Hart, Steven N., He, Wei, Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J., Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Johnson, Nichola, Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kaczmarek, Katarzyna, Kataja, Vesa, Keeman, Renske, Kerin, Michael J., Khusnutdinova, Elza, Kiiski, Johanna, I, Knight, Julia A., Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kristensen, Vessela N., Kruger, Ute, Kuehl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Lilyquist, Jenna, Lindblom, Annika, Lindstrom, Sara, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Long, Jirong, Lubinski, Jan, Lux, Michael P., MacInnis, Robert J., Maishman, Tom, Makalic, Enes, Kostovska, Ivana Maleva, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Menon, Usha, Middha, Pooja, Miller, Nicola, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Munoz-Garzon, Victor M., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Nielsen, Sune F., Nordestgaard, Borge G., Norman, Aaron, Offit, Kenneth, Olson, Janet E., Olsson, Hakan, Orr, Nick, Pankratz, V. Shane, Park-Simon, Tjoung-Won, Perez, Jose I. A., Perez-Barrios, Clara, Peterlongo, Paolo, Peto, Julian, Pinchev, Mila, Plaseska-Karanfilska, Dijana, Polley, Eric C., Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Purrington, Kristen, Pylkas, Katri, Rack, Brigitte, Radice, Paolo, Rau-Murthy, Rohini, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Robson, Mark, Romero, Atocha, Ruddy, Kathryn J., Ruebner, Matthias, Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schumacher, Fredrick, Schuermann, Peter, Schwentner, Lukas, Scott, Christopher, Scott, Rodney J., Seynaeve, Caroline, Shah, Mitul, Sherman, Mark E., Shrubsole, Martha J., Shu, Xiao-Ou, Slager, Susan, Smeets, Ann, Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Stegmaier, Christa, Stone, Jennifer, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Thoene, Kathrin, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Therese, Tzardi, Maria, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine M., van Veen, Elke M., Vijai, Joseph, Weinberg, Clarice R., Wendt, Camilla, Whittemore, Alice S., Wildiers, Hans, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Ziogas, Argyrios, Clarke, Christine, Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Sexton, Adrienne, Dobrovic, Alex, Christian, Alice, Trainer, Alison, Fellows, Andrew, Shelling, Andrew, De Fazio, Anna, Blackburn, Anneke, Crook, Ashley, Meiser, Bettina, Patterson, Briony, Clarke, Christobel, Saunders, Christobel, Hunt, Clare, Scott, Clare, Amor, David, Ortega, David Gallego, Marsh, Deb, Edkins, Edward, Salisbury, Elizabeth, Haan, Eric, Macrea, Finlay, Farshid, Gelareh, Lindeman, Geoff, Trench, Georgia, Mann, Graham, Giles, Graham, Gill, Grantley, Thorne, Heather, Campbell, Ian, Hickie, Ian, Caldon, Liz, Winship, Ingrid, Cui, James, Flanagan, James, Kollias, James, Visvader, Jane, Taylor, Jessica, Burke, Jo, Saunus, Jodi, Forbs, John, Hopper, John, Beesley, Jonathan, Kirk, Judy, French, Juliet, Tucker, Kathy, Wu, Kathy, Phillips, Kelly, Forrest, Laura, Lipton, Lara, Andrews, Leslie, Lobb, Lizz, Walker, Logan, Kentwell, Maira, Spurdle, Mandy, Cummings, Margaret, Gleeson, Margaret, Harris, Marion, Jenkins, Mark, Young, Mary Anne, Delatycki, Martin, Wallis, Mathew, Burgess, Matthew, Brown, Melissa, Southey, Melissa, Bogwitz, Michael, Field, Michael, Friedlander, Michael, Gattas, Michael, Saleh, Mona, Aghmesheh, Morteza, Hayward, Nick, Pachter, Nick, Cohen, Paul, Duijf, Pascal, James, Paul, Simpson, Pete, Fong, Peter, Butow, Phyllis, Williams, Rachael, Kefford, Rick, Simard, Jacques, Balleine, Rose-Mary, Dawson, Sarah-Jane, Lok, Sheau, O'connell, Shona, Greening, Sian, Nightingale, Sophie, Edwards, Stacey, Fox, Stephen, McLachlan, Sue-Anne, Lakhani, Sunil, Dudding, Tracy, Antill, Yoland, Sahlberg, Kristine K., Ottestad, Lars, Karesen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebraten, Olav, Naume, Bjorn, Fossa, Alexander, Kiserud, Cecile E., Reinertsen, Kristin, V, Helland, Aslaug, Riis, Margit, Geisler, Juergen, Dunning, Alison M., Thompson, Deborah J., Chenevix-Trench, Georgia, Chang-Claude, Jenny, Schmidt, Marjanka K., Hall, Per, Milne, Roger L., Pharoah, Paul D. P., Antoniou, Antonis C., Chatterjee, Nilanjan, Kraft, Peter, Garcia-Closas, Montserrat, and Easton, Douglas F.

Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Published
2019

31. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

Author

George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Mueller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurelien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Aslaug, Solberg, Steinar, Ansen, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Jorg, Wolf, Jurgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Buettner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, Thomas, Roman K., George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Mueller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurelien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Aslaug, Solberg, Steinar, Ansen, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Jorg, Wolf, Jurgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Buettner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, and Thomas, Roman K.

Abstract

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: type I LCNECs with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and type II LCNECs enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1(high)/DLL3(high)/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1l(ow)/DLL3(low)/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Published
2018

34. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

Author

Weischenfeldt, Joachim, Dubash, Taronish, Drainas, Alexandros P., Mardin, Balca R., Chen, Yuanyuan, Stuetz, Adrian M., Waszak, Sebastian M., Bosco, Graziella, Halvorsen, Ann Rita, Raeder, Benjamin, Efthymiopoulos, Theocharis, Erkek, Serap, Siegl, Christine, Brenner, Hermann, Brustugun, Odd Terje, Dieter, Sebastian M., Northcott, Paul A., Petersen, Iver, Pfister, Stefan M., Schneider, Martin, Solberg, Steinar K., Thunissen, Erik, Weichert, Wilko, Zichner, Thomas, Thomas, Roman, Peifer, Martin, Helland, Aslaug, Ball, Claudia R., Jechlinger, Martin, Sotillo, Rocio, Glimm, Hanno, Korbel, Jan O., Weischenfeldt, Joachim, Dubash, Taronish, Drainas, Alexandros P., Mardin, Balca R., Chen, Yuanyuan, Stuetz, Adrian M., Waszak, Sebastian M., Bosco, Graziella, Halvorsen, Ann Rita, Raeder, Benjamin, Efthymiopoulos, Theocharis, Erkek, Serap, Siegl, Christine, Brenner, Hermann, Brustugun, Odd Terje, Dieter, Sebastian M., Northcott, Paul A., Petersen, Iver, Pfister, Stefan M., Schneider, Martin, Solberg, Steinar K., Thunissen, Erik, Weichert, Wilko, Zichner, Thomas, Thomas, Roman, Peifer, Martin, Helland, Aslaug, Ball, Claudia R., Jechlinger, Martin, Sotillo, Rocio, Glimm, Hanno, and Korbel, Jan O.

Abstract

Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADS). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

Published
2017

35. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

Author

Weischenfeldt, Joachim Lütken, Dubash, Taronish, Drainas, Alexandros P, Mardin, Balca R, Chen, Yuanyuan, Stütz, Adrian M, Waszak, Sebastian M, Bosco, Graziella, Halvorsen, Ann Rita, Raeder, Benjamin, Efthymiopoulos, Theocharis, Erkek, Serap, Siegl, Christine, Brenner, Hermann, Brustugun, Odd Terje, Dieter, Sebastian M, Northcott, Paul A, Petersen, Iver, Pfister, Stefan M, Schneider, Martin, Solberg, Steinar K, Thunissen, Erik, Weichert, Wilko, Zichner, Thomas, Thomas, Roman, Peifer, Martin, Helland, Aslaug, Ball, Claudia R, Jechlinger, Martin, Sotillo, Rocio, Glimm, Hanno, Korbel, Jan O, Weischenfeldt, Joachim Lütken, Dubash, Taronish, Drainas, Alexandros P, Mardin, Balca R, Chen, Yuanyuan, Stütz, Adrian M, Waszak, Sebastian M, Bosco, Graziella, Halvorsen, Ann Rita, Raeder, Benjamin, Efthymiopoulos, Theocharis, Erkek, Serap, Siegl, Christine, Brenner, Hermann, Brustugun, Odd Terje, Dieter, Sebastian M, Northcott, Paul A, Petersen, Iver, Pfister, Stefan M, Schneider, Martin, Solberg, Steinar K, Thunissen, Erik, Weichert, Wilko, Zichner, Thomas, Thomas, Roman, Peifer, Martin, Helland, Aslaug, Ball, Claudia R, Jechlinger, Martin, Sotillo, Rocio, Glimm, Hanno, and Korbel, Jan O

Abstract

Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

Published
2017

36. Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study.

Author

Gandara, David R., primary, Von Pawel, Joachim, additional, Sullivan, Richard N., additional, Helland, Aslaug, additional, Han, Ji-Youn, additional, Ponce Aix, Santiago, additional, Rittmeyer, Achim, additional, Barlesi, Fabrice, additional, Kubo, Toshio, additional, Park, Keunchil, additional, Goldschmidt, Jerome H., additional, Gandhi, Mayank, additional, Yun, Cindy, additional, Yu, Wei, additional, Matheny, Christina, additional, He, Pei, additional, Sandler, Alan, additional, Ballinger, Marcus, additional, and Fehrenbacher, Louis, additional

Published
2017
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37. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author

Dunning, Alison M., Michailidou, Kyriaki, Kuchenbaecker, Karoline B., Thompson, Deborah, French, Juliet D., Beesley, Jonathan, Healey, Catherine S., Kar, Siddhartha, Pooley, Karen A., Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A., Sallari, Richard C., Hillman, Kristine M., Kaufmann, Susanne, Sivakumaran, Haran, Marjaneh, Mahdi Moradi, Lee, Jason S., Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K., Dennis, Joe, Wang, Qin, Hopper, John L., Southey, Melissa C., Broeks, Annegien, Schmidt, Marjanka K., Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W., Fasching, Peter A., dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal, Truong, Therese, Bojesen, Stig E., Flyger, Henrik, Gonzalez-Neira, Anna, Perez, Jose I. A., Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Hamann, Ute, Aittomaki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dork, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-chen, Wu, Anna H., Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E., Giles, Graham G., Milne, Roger L., Haiman, Christopher A., Henderson, Brian E., Goldberg, Mark S., Teo, Soo H., Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkas, Katri, Winqvist, Robert, Andrulis, Irene L., Knight, Julia A., Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E., Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans M. W., Humphreys, Keith, Gao, Yu-Tang, Shu, Xiao-Ou, Cox, Angela, Cross, Simon S., Blot, William, Cai, Qiuyin, Ghoussaini, Maya, Perkins, Barbara J., Shah, Mitul, Choi, Ji-Yeob, Kang, Daehee, Lee, Soo Chin, Hartman, Mikael, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Brennan, Paul, Sangrajrang, Suleeporn, Ambrosone, Christine B., Toland, Amanda E., Shen, Chen-Yang, Wu, Pei-Ei, Orr, Nick, Swerdlow, Anthony, McGuffog, Lesley, Healey, Sue, Lee, Andrew, Kapuscinski, Miroslav, John, Esther M., Terry, Mary Beth, Daly, Mary B., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ejlertsen, Bent, Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Rando, Rachel, Weitzel, Jeffrey N., Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Papi, Laura, Ottini, Laura, Konstantopoulou, Irene, Apostolou, Paraskevi, Garber, Judy, Rashid, Muhammad Usman, Frost, Debra, Izatt, Louise, Ellis, Steve, Godwin, Andrew K., Arnold, Norbert, Niederacher, Dieter, Rhiem, Kerstin, Bogdanova-Markov, Nadja, Sagne, Charlotte, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Sinilnikova, Olga M., Mazoyer, Sylvie, Isaacs, Claudine, Claes, Kathleen B. M., De Leeneer, Kim, De la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Khan, Sofia, Mensenkamp, Arjen R., Hooning, Maartje J., Rookus, Matti A., Kwong, Ava, Olah, Edith, Diez, Orland, Brunet, Joan, Pujana, Miquel Angel, Gronwald, Jacek, Huzarski, Tomasz, Barkardottir, Rosa B., Laframboise, Rachel, Soucy, Penny, Montagna, Marco, Agata, Simona, Teixeira, Manuel R., Park, Sue Kyung, Lindor, Noralane, Couch, Fergus J., Tischkowitz, Marc, Foretova, Lenka, Vijai, Joseph, Offit, Kenneth, Singer, Christian F., Rappaport, Christine, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Hulick, Peter J., Phillips, Kelly-Anne, Piedmonte, Marion, Mulligan, Anna Marie, Glendon, Gord, Bojesen, Anders, Thomassen, Mads, Caligo, Maria A., Yoon, Sook-Yee, Friedman, Eitan, Laitman, Yael, Borg, Ake, Von Wachenfeldt, Anna, Ehrencrona, Hans, Rantala, Johanna, Olopade, Olufunmilayo I., Ganz, Patricia A., Nussbaum, Robert L., Gayther, Simon A., Nathanson, Katherine L., Domchek, Susan M., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Maskarinec, Gertraud, Woolcott, Christy, Scott, Christopher, Stone, Jennifer, Apicella, Carmel, Tamimi, Rulla, Luben, Robert, Khaw, Kay-Tee, Helland, Aslaug, Haakensen, Vilde, Dowsett, Mitch, Pharoah, Paul D. P., Simard, Jacques, Hall, Per, Garcia-Closas, Montserrat, Vachon, Celine, Chenevix-Trench, Georgia, Antoniou, Antonis C., Easton, Douglas F., Edwards, Stacey L., Dunning, Alison M., Michailidou, Kyriaki, Kuchenbaecker, Karoline B., Thompson, Deborah, French, Juliet D., Beesley, Jonathan, Healey, Catherine S., Kar, Siddhartha, Pooley, Karen A., Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A., Sallari, Richard C., Hillman, Kristine M., Kaufmann, Susanne, Sivakumaran, Haran, Marjaneh, Mahdi Moradi, Lee, Jason S., Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K., Dennis, Joe, Wang, Qin, Hopper, John L., Southey, Melissa C., Broeks, Annegien, Schmidt, Marjanka K., Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W., Fasching, Peter A., dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal, Truong, Therese, Bojesen, Stig E., Flyger, Henrik, Gonzalez-Neira, Anna, Perez, Jose I. A., Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Hamann, Ute, Aittomaki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dork, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-chen, Wu, Anna H., Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E., Giles, Graham G., Milne, Roger L., Haiman, Christopher A., Henderson, Brian E., Goldberg, Mark S., Teo, Soo H., Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkas, Katri, Winqvist, Robert, Andrulis, Irene L., Knight, Julia A., Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E., Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans M. W., Humphreys, Keith, Gao, Yu-Tang, Shu, Xiao-Ou, Cox, Angela, Cross, Simon S., Blot, William, Cai, Qiuyin, Ghoussaini, Maya, Perkins, Barbara J., Shah, Mitul, Choi, Ji-Yeob, Kang, Daehee, Lee, Soo Chin, Hartman, Mikael, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Brennan, Paul, Sangrajrang, Suleeporn, Ambrosone, Christine B., Toland, Amanda E., Shen, Chen-Yang, Wu, Pei-Ei, Orr, Nick, Swerdlow, Anthony, McGuffog, Lesley, Healey, Sue, Lee, Andrew, Kapuscinski, Miroslav, John, Esther M., Terry, Mary Beth, Daly, Mary B., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ejlertsen, Bent, Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Rando, Rachel, Weitzel, Jeffrey N., Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Papi, Laura, Ottini, Laura, Konstantopoulou, Irene, Apostolou, Paraskevi, Garber, Judy, Rashid, Muhammad Usman, Frost, Debra, Izatt, Louise, Ellis, Steve, Godwin, Andrew K., Arnold, Norbert, Niederacher, Dieter, Rhiem, Kerstin, Bogdanova-Markov, Nadja, Sagne, Charlotte, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Sinilnikova, Olga M., Mazoyer, Sylvie, Isaacs, Claudine, Claes, Kathleen B. M., De Leeneer, Kim, De la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Khan, Sofia, Mensenkamp, Arjen R., Hooning, Maartje J., Rookus, Matti A., Kwong, Ava, Olah, Edith, Diez, Orland, Brunet, Joan, Pujana, Miquel Angel, Gronwald, Jacek, Huzarski, Tomasz, Barkardottir, Rosa B., Laframboise, Rachel, Soucy, Penny, Montagna, Marco, Agata, Simona, Teixeira, Manuel R., Park, Sue Kyung, Lindor, Noralane, Couch, Fergus J., Tischkowitz, Marc, Foretova, Lenka, Vijai, Joseph, Offit, Kenneth, Singer, Christian F., Rappaport, Christine, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Hulick, Peter J., Phillips, Kelly-Anne, Piedmonte, Marion, Mulligan, Anna Marie, Glendon, Gord, Bojesen, Anders, Thomassen, Mads, Caligo, Maria A., Yoon, Sook-Yee, Friedman, Eitan, Laitman, Yael, Borg, Ake, Von Wachenfeldt, Anna, Ehrencrona, Hans, Rantala, Johanna, Olopade, Olufunmilayo I., Ganz, Patricia A., Nussbaum, Robert L., Gayther, Simon A., Nathanson, Katherine L., Domchek, Susan M., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Maskarinec, Gertraud, Woolcott, Christy, Scott, Christopher, Stone, Jennifer, Apicella, Carmel, Tamimi, Rulla, Luben, Robert, Khaw, Kay-Tee, Helland, Aslaug, Haakensen, Vilde, Dowsett, Mitch, Pharoah, Paul D. P., Simard, Jacques, Hall, Per, Garcia-Closas, Montserrat, Vachon, Celine, Chenevix-Trench, Georgia, Antoniou, Antonis C., Easton, Douglas F., and Edwards, Stacey L.

Abstract

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression., Funding: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: A. Berchuck (OCAC), R.A. Eeles, A. A. Al Olama, Z. Kote-Jarai and S. Benlloch (PRACTICAL), C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissiere, F. Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, S. F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S. A. Windebank, C. A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Normal human tissues from the Susan G. Komen for the Cure Tissue Bank at the Indiana University Simon Cancer Center (Indianapolis) were used in this study. We thank the contributors, including Indiana University who collected samples used in this study, as well as the donors and their families, whose help and participation made this work possible. We also acknowledge National Institute for Health Research (NIHR) support to the Royal Marsden Biomedical Research Centre. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (NIH; CA128978, CA192393, CA116167, CA176785 and an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112, the GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Famili

Published
2016
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38. Inference of Tumor Evolution during Chemotherapy by Computational Modeling and In Situ Analysis of Genetic and Phenotypic Cellular Diversity

Author

Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Physics, Koch Institute for Integrative Cancer Research at MIT, Itzkovitz, Shalev, van Oudenaarden, Alexander, Almendro, Vanessa, Cheng, Yu-Kang, Randles, Amanda, Marusyk, Andriy, Ametller, Elisabet, Gonzalez-Farre, Xavier, Russnes, Hege G., Rye, Inga H., Borresen-Dale, Anne-Lise, Maruyama, Reo, Dowsett, Mitchell, Jones, Robin L., Reis-Filho, Jorge, Gascon, Pere, Michor, Franziska, Polyak, Kornelia, Munoz, Montse, Helland, Aslaug, Gonen, Mithat, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Physics, Koch Institute for Integrative Cancer Research at MIT, Itzkovitz, Shalev, van Oudenaarden, Alexander, Almendro, Vanessa, Cheng, Yu-Kang, Randles, Amanda, Marusyk, Andriy, Ametller, Elisabet, Gonzalez-Farre, Xavier, Russnes, Hege G., Rye, Inga H., Borresen-Dale, Anne-Lise, Maruyama, Reo, Dowsett, Mitchell, Jones, Robin L., Reis-Filho, Jorge, Gascon, Pere, Michor, Franziska, Polyak, Kornelia, Munoz, Montse, Helland, Aslaug, and Gonen, Mithat

Abstract

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution., National Cancer Institute (U.S.). Physical Sciences Oncology Center (U54CA143874)

Published
2016

39. The cellular proteome of pancreatic ductal adenocarcinoma

Author

Silwal-Pandit, Laxmi, Johansson, Henrik, Stålberg, Stina M., Mermelekas, Georgios, Bowitz Lothe, Inger-Marie, Skrede, Martina L., Dalsgaard, Astrid M., Helland, Åslaug, Skålhegg, Bjørn S., Labori, Knut Jørgen, Lingjærde, Ole Christian, Lehtiö, Janne, and Kure, Elin

Published
2019
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40. p53 polymorphism and cervical cancer

Author

Helland, Aslaug, Borresen-Dale, Anne-Lise, Zehbe, Ingeborg, Voglino, Gianfranco, Wilander, Erik, Genta, Franco, and Tommasino, Massimo

Subjects
Tumor suppressor genes -- Physiological aspects, Cervical cancer -- Development and progression
Published
1999

41. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

Author

Weischenfeldt, Joachim, primary, Dubash, Taronish, additional, Drainas, Alexandros P, additional, Mardin, Balca R, additional, Chen, Yuanyuan, additional, Stütz, Adrian M, additional, Waszak, Sebastian M, additional, Bosco, Graziella, additional, Halvorsen, Ann Rita, additional, Raeder, Benjamin, additional, Efthymiopoulos, Theocharis, additional, Erkek, Serap, additional, Siegl, Christine, additional, Brenner, Hermann, additional, Brustugun, Odd Terje, additional, Dieter, Sebastian M, additional, Northcott, Paul A, additional, Petersen, Iver, additional, Pfister, Stefan M, additional, Schneider, Martin, additional, Solberg, Steinar K, additional, Thunissen, Erik, additional, Weichert, Wilko, additional, Zichner, Thomas, additional, Thomas, Roman, additional, Peifer, Martin, additional, Helland, Aslaug, additional, Ball, Claudia R, additional, Jechlinger, Martin, additional, Sotillo, Rocio, additional, Glimm, Hanno, additional, and Korbel, Jan O, additional

Published
2016
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43. Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism

Author

Witek, Barbara, El Wakil, Abeer, Nord, Christoffer, Ahlgren, Ulf, Eriksson, Maria, Vernersson-Lindahl, Emma, Helland, Aslaug, Alexeyev, Oleg A., Hallberg, Bengt, Palmer, Ruth H., Witek, Barbara, El Wakil, Abeer, Nord, Christoffer, Ahlgren, Ulf, Eriksson, Maria, Vernersson-Lindahl, Emma, Helland, Aslaug, Alexeyev, Oleg A., Hallberg, Bengt, and Palmer, Ruth H.

Abstract

Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

Published
2015
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44. Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Author

Fernandez-Cuesta, Lynnette, Sun, Ruping, Menon, Roopika, George, Julie, Lorenz, Susanne, Meza-Zepeda, Leonardo A., Peifer, Martin, Plenker, Dennis, Heuckmann, Johannes M., Leenders, Frauke, Zander, Thomas, Dahmen, Ilona, Koker, Mirjam, Schoettle, Jakob, Ullrich, Roland T., Altmueller, Janine, Becker, Christian, Nuernberg, Peter, Seidel, Henrik, Boehm, Diana, Goeke, Friederike, Ansen, Sascha, Russell, Prudence A., Wright, Gavin M., Wainer, Zoe, Solomon, Benjamin, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Brustugun, Odd-Terje, Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Buettner, Reinhard, Wolf, Juergen, Brambilla, Elisabeth, Vingron, Martin, Perner, Sven, Haas, Stefan A., Thomas, Roman K., Fernandez-Cuesta, Lynnette, Sun, Ruping, Menon, Roopika, George, Julie, Lorenz, Susanne, Meza-Zepeda, Leonardo A., Peifer, Martin, Plenker, Dennis, Heuckmann, Johannes M., Leenders, Frauke, Zander, Thomas, Dahmen, Ilona, Koker, Mirjam, Schoettle, Jakob, Ullrich, Roland T., Altmueller, Janine, Becker, Christian, Nuernberg, Peter, Seidel, Henrik, Boehm, Diana, Goeke, Friederike, Ansen, Sascha, Russell, Prudence A., Wright, Gavin M., Wainer, Zoe, Solomon, Benjamin, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Brustugun, Odd-Terje, Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Buettner, Reinhard, Wolf, Juergen, Brambilla, Elisabeth, Vingron, Martin, Perner, Sven, Haas, Stefan A., and Thomas, Roman K.

Abstract

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.

Published
2015

45. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors

Author

Fernandez-Cuesta, Lynnette, Peifer, Martin, George, Julie, De Reynies, Aurelien, Sun, Ruping, Altmueller, Janine, Nuernberg, Peter, Olivier, Magali, Ardin, Maude, Blum, Yuna, Laffaire, Julien, Elarouci, Nabila, Petel, Fabien, Mckay, James, Byrnes, Graham, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian, Lantuejoul, Sylvie, Mcleer, Anne, Soltermann, Alex, Brustugun, Odd T., Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Ansen, Sascha, Wright, Gavin, Russell, Prudence A., Solomon, Benjamin J., Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Zander, Thomas, Buettner, Reinhard, Haas, Stefan, Brambilla, Elisabeth, Thomas, Roman K., Fernandez-Cuesta, Lynnette, Peifer, Martin, George, Julie, De Reynies, Aurelien, Sun, Ruping, Altmueller, Janine, Nuernberg, Peter, Olivier, Magali, Ardin, Maude, Blum, Yuna, Laffaire, Julien, Elarouci, Nabila, Petel, Fabien, Mckay, James, Byrnes, Graham, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian, Lantuejoul, Sylvie, Mcleer, Anne, Soltermann, Alex, Brustugun, Odd T., Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Ansen, Sascha, Wright, Gavin, Russell, Prudence A., Solomon, Benjamin J., Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Zander, Thomas, Buettner, Reinhard, Haas, Stefan, Brambilla, Elisabeth, and Thomas, Roman K.

Published
2015

46. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Author

Darabi, Hatef, Mccue, Karen, Beesley, Jonathan, Michailidou, Kyriaki, Nord, Silje, Kar, Siddhartha, Humphreys, Keith, Thompson, Deborah, Ghoussaini, Maya, Bolla, Manjeet K., Dennis, Joe, Wang, Qin, Canisius, Sander, Scott, Christopher G., Apicella, Carmel, Hopper, John L., Southey, Melissa C., Stone, Jennifer, Broeks, Annegien, Schmidt, Marjanka K., Scott, Rodney J., Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W., Ekici, Arif B., Fasching, Peter A., Heusinger, Katharina, dos-Santos-Silva, Isabel, Peto, Julian, Tomlinson, Ian, Sawyer, Elinor J., Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal, Truong, Therese, Bojesen, Stig E., Flyger, Henrik, Benitez, Javier, Gonzalez-Neira, Anna, Anton-Culver, Hoda, Neuhausen, Susan L., Arndt, Volker, Brenner, Hermann, Engel, Christoph, Meindl, Alfons, Schmutzler, Rita K., Arnold, Norbert, Brauch, Hiltrud, Hamann, Ute, Chang-Claude, Jenny, Khan, Sofia, Nevanlinna, Heli, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natalia V., Doerk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H., Floris, Giuseppe, Lambrechts, Diether, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Couch, Fergus J., Vachon, Celine, Giles, Graham G., McLean, Catriona, Milne, Roger L., Dugue, Pierre-Antoine, Haiman, Christopher A., Maskarinec, Gertraud, Woolcott, Christy, Henderson, Brian E., Goldberg, Mark S., Simard, Jacques, Teo, Soo H., Mariapun, Shivaani, Helland, Aslaug, Haakensen, Vilde, Zheng, Wei, Beeghly-Fadiel, Alicia, Tamimi, Rulla, Jukkola-Vuorinen, Aria, Winqvist, Robert, Andrulis, Irene L., Knight, Julia A., Devilee, Peter, Tollenaar, Robert A. E. M., Figueroa, Jonine, Garcia-Closas, Montserrat, Czene, Kamila, Hooning, Maartje J., Tilanus-Linthorst, Madeleine, Li, Jingmei, Gao, Yu-Tang, Shu, Xiao-Ou, Cox, Angela, Cross, Simon S., Luben, Robert, Khaw, Kay-Tee, Choi, Ji-Yeob, Kang, Daehee, Hartman, Mikael, Lim, Wei Yen, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, McKay, James, Sangrajrang, Suleeporn, Toland, Amanda E., Yannoukakos, Drakoulis, Shen, Chen-Yang, Yu, Jyh-Cherng, Ziogas, Argyrios, Schoemaker, Minouk J., Swerdlow, Anthony, Borresen-Dale, Anne-Lise, Kristensen, Vessela, French, Juliet D., Edwards, Stacey L., Dunning, Alison M., Easton, Douglas F., Hal, Per, Chenevix-Trench, Georgia, Darabi, Hatef, Mccue, Karen, Beesley, Jonathan, Michailidou, Kyriaki, Nord, Silje, Kar, Siddhartha, Humphreys, Keith, Thompson, Deborah, Ghoussaini, Maya, Bolla, Manjeet K., Dennis, Joe, Wang, Qin, Canisius, Sander, Scott, Christopher G., Apicella, Carmel, Hopper, John L., Southey, Melissa C., Stone, Jennifer, Broeks, Annegien, Schmidt, Marjanka K., Scott, Rodney J., Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W., Ekici, Arif B., Fasching, Peter A., Heusinger, Katharina, dos-Santos-Silva, Isabel, Peto, Julian, Tomlinson, Ian, Sawyer, Elinor J., Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal, Truong, Therese, Bojesen, Stig E., Flyger, Henrik, Benitez, Javier, Gonzalez-Neira, Anna, Anton-Culver, Hoda, Neuhausen, Susan L., Arndt, Volker, Brenner, Hermann, Engel, Christoph, Meindl, Alfons, Schmutzler, Rita K., Arnold, Norbert, Brauch, Hiltrud, Hamann, Ute, Chang-Claude, Jenny, Khan, Sofia, Nevanlinna, Heli, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natalia V., Doerk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H., Floris, Giuseppe, Lambrechts, Diether, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Couch, Fergus J., Vachon, Celine, Giles, Graham G., McLean, Catriona, Milne, Roger L., Dugue, Pierre-Antoine, Haiman, Christopher A., Maskarinec, Gertraud, Woolcott, Christy, Henderson, Brian E., Goldberg, Mark S., Simard, Jacques, Teo, Soo H., Mariapun, Shivaani, Helland, Aslaug, Haakensen, Vilde, Zheng, Wei, Beeghly-Fadiel, Alicia, Tamimi, Rulla, Jukkola-Vuorinen, Aria, Winqvist, Robert, Andrulis, Irene L., Knight, Julia A., Devilee, Peter, Tollenaar, Robert A. E. M., Figueroa, Jonine, Garcia-Closas, Montserrat, Czene, Kamila, Hooning, Maartje J., Tilanus-Linthorst, Madeleine, Li, Jingmei, Gao, Yu-Tang, Shu, Xiao-Ou, Cox, Angela, Cross, Simon S., Luben, Robert, Khaw, Kay-Tee, Choi, Ji-Yeob, Kang, Daehee, Hartman, Mikael, Lim, Wei Yen, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, McKay, James, Sangrajrang, Suleeporn, Toland, Amanda E., Yannoukakos, Drakoulis, Shen, Chen-Yang, Yu, Jyh-Cherng, Ziogas, Argyrios, Schoemaker, Minouk J., Swerdlow, Anthony, Borresen-Dale, Anne-Lise, Kristensen, Vessela, French, Juliet D., Edwards, Stacey L., Dunning, Alison M., Easton, Douglas F., Hal, Per, and Chenevix-Trench, Georgia

Abstract

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 10.82-0.881) and ER-negative (OR = 0.87 [0.82-0.911) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:0) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 10.91-0.951 and OR = 1.06 [1.03-1.091) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.131) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.961). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Published
2015

47. IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.

Author

Helland, Aslaug, Smeland, Sigbjørn, Russnes, Hege, Brabrand, Sigmund, Puco, Katarina, Niehusmann, Pitt, Cameron, Marte Grønlie, Blix, Egil, Haug, Ase, Oppdal, Irja Alida, Heinrich, Daniel, Meltzer, Sebastian, Flobak, Åsmund, Steinskog, Eli Sihn, Torkildsen, Cecilie Fredvik, Fagereng, Gro Live, Dalhaug, Astrid, Hjortland, Geir Olav, Bjørge, Line, and Tasken, Kjetil

Published
2023
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48. Sex differences in burden of adverse events in patients receiving immunotherapy.

Author

Miceli, Rosalba, Eriksson, Hanna, Eustace, Alex J., Lo Russo, Giuseppe, Alfieri, Salvatore, Bjaanæs, Maria Moksnes, Pietrantonio, Filippo, De Cecco, Loris, Prelaj, Arsela, Proto, Claudia, Franzen, Johan, McDonnell, Deirdre, Berenguer Pina, Jose Javier, Beninato, Teresa, Mazzeo, Laura, Giannatempo, Patrizia, Verzoni, Elena, Crown, John, and Helland, Aslaug

Published
2023
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49. Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Author

Donnem, Tom, primary, Hald, Sigurd M., additional, Paulsen, Erna-Elise, additional, Richardsen, Elin, additional, Al-Saad, Samer, additional, Kilvaer, Thomas K., additional, Brustugun, Odd Terje, additional, Helland, Aslaug, additional, Lund-Iversen, Marius, additional, Poehl, Mette, additional, Olsen, Karen Ege, additional, Ditzel, Henrik J., additional, Hansen, Olfred, additional, Al-Shibli, Khalid, additional, Kiselev, Yury, additional, Sandanger, Torkjel M., additional, Andersen, Sigve, additional, Pezzella, Francesco, additional, Bremnes, Roy M., additional, and Busund, Lill-Tove, additional

Published
2015
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50. Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis

Author

Fleischer, Thomas, Frigessi, Arnoldo, Johnson, Kevin C., Edvardsen, Hege, Touleimat, Nizar, Klajic, Jovana, Riis, Margit L. H., Haakensen, Vilde D., Wärnberg, Fredrik, Naume, Bjorn, Helland, Aslaug, Borresen-Dale, Anne-Lise, Tost, Jorg, Christensen, Brock C., Kristensen, Vessela N., Fleischer, Thomas, Frigessi, Arnoldo, Johnson, Kevin C., Edvardsen, Hege, Touleimat, Nizar, Klajic, Jovana, Riis, Margit L. H., Haakensen, Vilde D., Wärnberg, Fredrik, Naume, Bjorn, Helland, Aslaug, Borresen-Dale, Anne-Lise, Tost, Jorg, Christensen, Brock C., and Kristensen, Vessela N.

Abstract

Background: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.

Published
2014
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