Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. Morra, A., Escala-Garcia, M., Beesley, J., Keeman, R., Canisius, S., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Augustinsson, A., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Bojesen, S. E., Bolla, M. K., Brenner, H., Brüning, T., Buys, S. S., Caan, B., Campa, D., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Cheng, T. D., Clarke, C. L., NBCS Collaborators, Colonna, S. V., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Dennis, J., Dörk, T., Dossus, L., Dunning, A. M., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Eriksson, M., Evans, D. G., Fasching, P. A., Flyger, H., Fritschi, L., Gago-Dominguez, M., García-Sáenz, J. A., Giles, G. G., Grip, M., Guénel, P., Gündert, M., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Hart, S. N., Hartikainen, J. M., Hartmann, A., He, W., Hooning, M. J., Hoppe, R., Hopper, J. L., Howell, A., Hunter, D. J., ABCTB Investigators, kConFab Investigators, Jager, A., Jakubowska, A., Janni, W., John, E. M., Jung, A. Y., Kaaks, R., Keupers, M., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kurian, A. W., Lacey, J. V., Lambrechts, D., Le Marchand, L., Lindblom, A., Linet, M., Luben, R. N., Lubiński, J., Lush, M., Mannermaa, A., Manoochehri, M., Margolin, S., Martens, J. W. M., Martinez, M. E., Mavroudis, D., Michailidou, K., Milne, R. L., Mulligan, A. M., Muranen, T. A., Nevanlinna, H., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Olshan, A. F., Olsson, H., Orr, N., Park-Simon, T., Patel, A. V., Peissel, B., Peterlongo, P., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Rack, B., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Ruebner, M., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schneeweiss, A., Scott, C., Shah, M., Smichkoska, S., Southey, M. C., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Teras, L. R., Terry, M. B., Tollenaar, R. A. E. M., Tomlinson, I., Troester, M. A., Truong, T., Vachon, C. M., Wang, Q., Hurson, A. N., Winqvist, R., Wolk, A., Ziogas, A., Brauch, H., García-Closas, M., Pharoah, P. D. P., Easton, D. F., Chenevix-Trench, G., & Schmidt, M. K. Breast cancer research: BCR, 23(1):86, August, 2021.
doi  abstract   bibtex   
BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP \textless 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
@article{morra_association_2021,
	title = {Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment},
	volume = {23},
	issn = {1465-542X},
	doi = {10.1186/s13058-021-01450-7},
	abstract = {BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.
METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP {\textless} 0.15).
RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95\% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95\% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95\% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95\% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.
CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.},
	language = {eng},
	number = {1},
	journal = {Breast cancer research: BCR},
	author = {Morra, Anna and Escala-Garcia, Maria and Beesley, Jonathan and Keeman, Renske and Canisius, Sander and Ahearn, Thomas U. and Andrulis, Irene L. and Anton-Culver, Hoda and Arndt, Volker and Auer, Paul L. and Augustinsson, Annelie and Beane Freeman, Laura E. and Becher, Heiko and Beckmann, Matthias W. and Behrens, Sabine and Bojesen, Stig E. and Bolla, Manjeet K. and Brenner, Hermann and Brüning, Thomas and Buys, Saundra S. and Caan, Bette and Campa, Daniele and Canzian, Federico and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Cheng, Ting-Yuan David and Clarke, Christine L. and {NBCS Collaborators} and Colonna, Sarah V. and Couch, Fergus J. and Cox, Angela and Cross, Simon S. and Czene, Kamila and Daly, Mary B. and Dennis, Joe and Dörk, Thilo and Dossus, Laure and Dunning, Alison M. and Dwek, Miriam and Eccles, Diana M. and Ekici, Arif B. and Eliassen, A. Heather and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Flyger, Henrik and Fritschi, Lin and Gago-Dominguez, Manuela and García-Sáenz, José A. and Giles, Graham G. and Grip, Mervi and Guénel, Pascal and Gündert, Melanie and Hahnen, Eric and Haiman, Christopher A. and Håkansson, Niclas and Hall, Per and Hamann, Ute and Hart, Steven N. and Hartikainen, Jaana M. and Hartmann, Arndt and He, Wei and Hooning, Maartje J. and Hoppe, Reiner and Hopper, John L. and Howell, Anthony and Hunter, David J. and {ABCTB Investigators} and {kConFab Investigators} and Jager, Agnes and Jakubowska, Anna and Janni, Wolfgang and John, Esther M. and Jung, Audrey Y. and Kaaks, Rudolf and Keupers, Machteld and Kitahara, Cari M. and Koutros, Stella and Kraft, Peter and Kristensen, Vessela N. and Kurian, Allison W. and Lacey, James V. and Lambrechts, Diether and Le Marchand, Loic and Lindblom, Annika and Linet, Martha and Luben, Robert N. and Lubiński, Jan and Lush, Michael and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Martens, John W. M. and Martinez, Maria Elena and Mavroudis, Dimitrios and Michailidou, Kyriaki and Milne, Roger L. and Mulligan, Anna Marie and Muranen, Taru A. and Nevanlinna, Heli and Newman, William G. and Nielsen, Sune F. and Nordestgaard, Børge G. and Olshan, Andrew F. and Olsson, Håkan and Orr, Nick and Park-Simon, Tjoung-Won and Patel, Alpa V. and Peissel, Bernard and Peterlongo, Paolo and Plaseska-Karanfilska, Dijana and Prajzendanc, Karolina and Prentice, Ross and Presneau, Nadege and Rack, Brigitte and Rennert, Gad and Rennert, Hedy S. and Rhenius, Valerie and Romero, Atocha and Roylance, Rebecca and Ruebner, Matthias and Saloustros, Emmanouil and Sawyer, Elinor J. and Schmutzler, Rita K. and Schneeweiss, Andreas and Scott, Christopher and Shah, Mitul and Smichkoska, Snezhana and Southey, Melissa C. and Stone, Jennifer and Surowy, Harald and Swerdlow, Anthony J. and Tamimi, Rulla M. and Tapper, William J. and Teras, Lauren R. and Terry, Mary Beth and Tollenaar, Rob A. E. M. and Tomlinson, Ian and Troester, Melissa A. and Truong, Thérèse and Vachon, Celine M. and Wang, Qin and Hurson, Amber N. and Winqvist, Robert and Wolk, Alicja and Ziogas, Argyrios and Brauch, Hiltrud and García-Closas, Montserrat and Pharoah, Paul D. P. and Easton, Douglas F. and Chenevix-Trench, Georgia and Schmidt, Marjanka K.},
	month = aug,
	year = {2021},
	pmid = {34407845},
	pmcid = {PMC8371820},
	keywords = {Breast Neoplasms, Breast cancer-specific survival, Common germline genetic variants, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Patient subgroups, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis, Systemic treatment, Tumor biology},
	pages = {86},
}
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