225 results on '"Figueroa JD"'
Search Results
2. Genome-wide association study identifies multiple loci associated with bladder cancer risk
- Author
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Figueroa, JD, Ye, Y, Siddiq, A, Garcia-Closas, M, Chatterjee, N, Prokunina-Olsson, L, Cortessis, VK, Kooperberg, C, Cussenot, O, Benhamou, S, Prescott, J, Porru, S, Dinney, CP, Malats, N, Baris, D, Purdue, M, Jacobs, EJ, Albanes, D, Wang, Z, Deng, X, Chung, CC, Tang, W, Bueno-De-Mesquita, HB, Trichopoulos, D, Ljungberg, B, Clavel-Chapelon, F, Weiderpass, E, Krogh, V, Dorronsoro, M, Travis, R, Tjonneland, A, Brenan, P, Chang-Claude, J, Riboli, E, Conti, D, Gago Dominguez, Manuela, Stern, MC, Pike, MC, Van den Berg, D, Yuan, JM, Hohensee, C, Rodabough, R, Cancel-Tassin, G, Roupret, M, Comperat, E, Chen, C, De Vivo, I, Giovannucci, E, Hunter, DJ, Kraft, P, Lindstrom, S, Carta, A, Pavanello, S, Arici, C, Mastrangelo, G, Kamat, AM, Lerner, SP, Grossman, HB, Lin, J, Gu, J, Pu, X, Hutchinson, A, Burdette, L, Wheeler, W, Kogevinas, M, Tardon, A, Serra, C, Carrato, A, Garcia-Closas, R, Lloreta, J, Schwenn, M, Karagas, MR, Johnson, A, Schned, A, Armenti, KR, Hosain, GM, Andriole, G, Grubb, R, Black, A, Diver, WR, Gapstur, SM, Weinstein, SJ, Virtamo, J, Haiman, CA, Landi, MT, Caporaso, N, Fraumeni, JF, Vineis, P, Wu, X, Silverman, DT, Chanock, S, and Rothman, N
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Risk ,Genotype ,Meta-Analysis as Topic ,Urinary Bladder Neoplasms ,Genetic Loci ,Case-Control Studies ,Humans ,Genetic Predisposition to Disease ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Genome-Wide Association Study - Abstract
Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 x 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 x 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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- 2014
3. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium
- Author
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Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, JI, Zamora, MP, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q (Qing), Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, YD, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, JM, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, MR, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, RX, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, Maartje, Kriege, Mieke, van den Ouweland, Ans, Koppert, Linetta, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, JR, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK (Marjanka), Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, JY, Park, SK, Noh, DY, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, WT, Shen, CY, Hsiung, CN, Yu, JC, Hou, MF, Guenel, P, Sanchez, M, Mulot, C, Blot, W, Cai, QY, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Bogdanova, N, Dork, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Shu, XO, Lu, W, Gao, YT, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, Mckay, J, Wang, XS, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S (Shahana), Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, Easton, DF, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Surgery
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SDG 3 - Good Health and Well-being - Abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
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- 2014
4. Magnetic Resonance Imaging Tracking of Distal Inflammatory Changes following Mild Traumatic Brain Injury (mTBI) in rats
- Author
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Gillham, SB, primary, Figueroa, JD, additional, and Bartnik, B, additional
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- 2016
- Full Text
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5. Abstract P5-02-04: Plasma autoantibodies associated with basal-like breast cancers
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Wang (Student), J, primary, Figueroa, JD, additional, Wallstrom, G, additional, Barker, K, additional, Park, JG, additional, Demirkan, G, additional, Lissowska, J, additional, Anderson, K, additional, Qiu, J, additional, and LaBaer, J, additional
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- 2016
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6. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the International Consortium of Bladder Cancer
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Stern, Mc, Lin, J, Figueroa, Jd, Kelsey, Kt, Kiltie, Ae, Yuan, J. M., Matullo, G, Fletcher, T, Benhamou, S, Taylor, Ja, Placidi, Donatella, Zhang, Zf, Steineck, G, Rothman, N, Kogevinas, M, Silverman, D, Malatas, N, Chanock, S, Wu, X, KARAGAS MR ANDREW AS, Nelson, Hh, Bishop, Dt, Sak, Sc, Choudhury, A, Barrett, Jh, Elliot, F, Corral, R, Joshi, Ad, GAGO DOMINGUEZ, M, Cortessis, Vk, Xiang, Yb, Vineis, P, Sacerdote, C, Guarrera, S, Polidoro, S, Allione, A, Gurzau, E, Koppova, K, Kumar, R, Rudnai, P, Porru, Stefano, Carta, Angela, Campagna, Marcello, Arici, Cecilia, Park, Sl, and GARCIA CLOSAS, M.
- Published
- 2009
7. Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive lifespan
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Warren Andersen, S, primary, Trentham-Dietz, A, additional, Gangnon, RE, additional, Hampton, JM, additional, Figueroa, JD, additional, Skinner, HG, additional, Engelman, CD, additional, Klein, BE, additional, Titus, LJ, additional, Egan, KM, additional, and Newcomb, PA, additional
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- 2013
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8. Abstract P3-08-02: Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets
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Horne, HN, primary, Sherman, ME, additional, Garcia-Closas, M, additional, Pharoah, PD, additional, Blows, FM, additional, Yang, XR, additional, Lissowska, J, additional, Brinton, LA, additional, Chanock, SJ, additional, and Figueroa, JD, additional
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- 2012
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9. Abstract P3-12-05: Genetic Variation in Prolactin and Prolactin Receptor, and Relationships with Serum Prolactin Levels and Breast Cancer Risk
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Nyante, SJ, primary, Faupel-Badger, JM, additional, Sherman, ME, additional, Gaudet, MM, additional, Falk, RT, additional, Andaya, AA, additional, Pfeiffer, RM, additional, Lissowska, J, additional, Brinton, LA, additional, Peplonska, B, additional, Vonderhaar, BK, additional, Chanock, SJ, additional, Garcia-Closas, M, additional, and Figueroa, JD., additional
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- 2010
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10. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
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Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. Helman, Yuh Min Chen, Ana Patiño-García, Pär Stattin, Xiaoping Miao, Tangchun Wu, Jay S. Wunder, Ann W. Hsing, Yu-Tang Gao, Brooke L. Fridley, Tania Carreón, Charles C. Chung, Nan Hu, Yoo Jin Jung, Richard B. Biritwum, Eric J. Duell, Philip R. Taylor, Satu Männistö, Kai Yu, Meredith Yeager, Xia Pu, Vittorio Krogh, Anand P. Chokkalingam, Susan M. Gapstur, W. Ryan Diver, Yuanqing Ye, Keitaro Matsuo, Cecilia Arici, You-Lin Qiao, Alan R. Schned, Dominique S. Michaud, Joanne W. Elena, Christopher Kim, Dongxin Lin, Yun-Chul Hong, Daru Lu, Reina García-Closas, Jonine D. Figueroa, Linda M. Liao, Yi-Long Wu, Heiner Boeing, Mark Lathrop, Göran Hallmans, Elizabeth A. Holly, Carol Giffen, Andrew A. Adjei, Consol Serra, Anne Tjønneland, Joseph F. Fraumeni, Alisa M. Goldstein, Ruth C. Travis, Rebecca Troisi, Dalsu Baris, Nalan Gokgoz, Olivier Cussenot, Xiang Deng, Yeul Hong Kim, Malin Sund, Sonja I. Berndt, E. David Crawford, Edward D. Yeboah, Sook Whan Sung, Françoise Clavel-Chapelon, Woon-Puay Koh, Nilgun Kurucu, Richard B. Hayes, Ashish M. Kamat, Beata Peplonska, Laurie Burdette, Ze Zhang Tang, Alan A. Arslan, Malcolm C. Pike, Sabina Sierri, J. Michael Gaziano, Lorna H. McNeil, Katherine A. McGlynn, Ulla Vogel, Logan G. Spector, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Jae Yong Park, Jennifer Prescott, Fernando Lecanda, Margaret A. Tucker, Ti Ding, Christian C. Abnet, Jenny Chang-Claude, Dimitrios Trichopoulos, Wei-Yen Lim, Wen Tan, Nick Orr, Jin Hee Kim, Stefano Porru, Chand Khanna, Robert R. McWilliams, Zhaoming Wang, Jeong Seon Ryu, David V. Conti, Alison P. Klein, Adonina Tardón, Robert J. Klein, Rebecca J. Rodabough, Mark H. Greene, Aruna Kamineni, Jie Lin, Rachael Z. Stolzenberg-Solomon, Patricia Hartge, Susan E. Hankinson, Young-Chul Kim, In Sam Kim, Luis Sierrasesúmaga, Roel Vermeulen, Paige M. Bracci, Mariana C. Stern, Louise A. Brinton, Myron D. Gross, Yong-Bing Xiang, Chih Yi Chen, G. A. Gerald Andriole, Paul S. Meltzer, Ying-Huang Tsai, Faith G. Davis, Ulrika Andersson, Paul Brennan, Sara Lindström, Chaoyu Wang, Giuseppe Mastrangelo, Laufey T. Amundadottir, Immaculata De Vivo, Bryan A. Bassig, Elisabete Weiderpass, Takashi Kohno, Nilanjan Chatterjee, Margaret R. Spitz, Pier Alberto Bertazzi, William Wheeler, David J. Hunter, Wei Tang, Qiuyin Cai, Naomi E. Allen, Molly Schwenn, Emily White, Min Shen, Adeline Seow, Laura E. Beane Freeman, James E. Mensah, Howard D. Sesso, Anna Luisa Di Stefano, Amanda Black, Manuela Gago-Dominguez, Christine B. Ambrosone, Avima M. Ruder, Martha S. Linet, Meir J. Stampfer, Robert C. Kurtz, Donald A. Barkauskas, Lisa W. Chu, Montserrat Garcia-Closas, Jason W. Hoskins, Melissa A. Austin, Kyoung Mu Lee, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Richard Gorlick, Piero Picci, Gianluca Severi, Ann G. Schwartz, Jian Gu, Christopher I. Amos, Marie-Christine Boutron-Ruault, Salvatore Panico, Alicja Wolk, Sara S. Strom, Lisa Mirabello, Jin-Hu Fan, Chin-Fu Hsiao, Neal D. Freedman, Geoffrey S. Tobias, Julie M. Gastier-Foster, Wang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, Cc, Sampson, Jn, Hoskins, Jw, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, P, Abnet, Cc, Adjei, Aa, Ahlbom, A, Albanes, D, Allen, Ne, Ambrosone, Cb, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole G., Jr, Andrulis, Il, Arici, C, Arslan, Aa, Austin, Ma, Baris, D, Barkauskas, Da, Bassig, Ba, Beane Freeman, Le, Berg, Cd, Berndt, Si, Bertazzi, Pa, Biritwum, Rb, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron Ruault, Mc, Bracci, Pm, Brennan, P, Brinton, La, Brotzman, M, Bueno de Mesquita, Hb, Buring, Je, Butler, Ma, Cai, Q, Cancel Tassin, G, Canzian, F, Cao, G, Caporaso, Ne, Carrato, A, Carreon, T, Carta, A, Chang, Gc, Chang, I, Chang Claude, J, Che, X, Chen, Cj, Chen, Cy, Chen, Ch, Chen, C, Chen, Ky, Chen, Ym, Chokkalingam, Ap, Chu, Lw, Clavel Chapelon, F, Colditz, Ga, Colt, J, Conti, D, Cook, Mb, Cortessis, Vk, Crawford, Ed, Cussenot, O, Davis, Fg, De Vivo, I, Deng, X, Ding, T, Dinney, Cp, Di Stefano, Al, Diver, Wr, Duell, Ej, Elena, Jw, Fan, Jh, Feigelson, H, Feychting, M, Figueroa, Jd, Flanagan, Am, Fraumeni JF, Jr, Freedman, Nd, Fridley, Bl, Fuchs, C, Gago Dominguez, M, Gallinger, S, Gao, Yt, Gapstur, Sm, Garcia Closas, M, Garcia Closas, R, Gastier Foster, Jm, Gaziano, Jm, Gerhard, D, Giffen, Ca, Giles, Gg, Gillanders, Em, Giovannucci, El, Goggins, M, Gokgoz, N, Goldstein, Am, Gonzalez, C, Gorlick, R, Greene, Mh, Gross, M, Grossman, Hb, Grubb R., 3rd, Gu, J, Guan, P, Haiman, Ca, Hallmans, G, Hankinson, Se, Harris, Cc, Hartge, P, Hattinger, C, Hayes, Rb, He, Q, Helman, L, Henderson, Be, Henriksson, R, Hoffman Bolton, J, Hohensee, C, Holly, Ea, Hong, Yc, Hoover, Rn, Hosgood HD, 3rd, Hsiao, Cf, Hsing, Aw, Hsiung, Ca, Hu, N, Hu, W, Hu, Z, Huang, M, Hunter, Dj, Inskip, Pd, Ito, H, Jacobs, Ej, Jacobs, Kb, Jenab, M, Ji, Bt, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, Am, Kamineni, A, Karagas, M, Khanna, C, Khaw, Kt, Kim, C, Kim, I, Kim, Yh, Kim, Yc, Kim, Yt, Kang, Ch, Jung, Yj, Kitahara, Cm, Klein, Ap, Klein, R, Kogevinas, M, Koh, Wp, Kohno, T, Kolonel, Ln, Kooperberg, C, Kratz, Cp, Krogh, V, Kunitoh, H, Kurtz, Rc, Kurucu, N, Lan, Q, Lathrop, M, Lau, Cc, Lecanda, F, Lee, Km, Lee, Mp, Le Marchand, L, Lerner, Sp, Li, D, Liao, Lm, Lim, Wy, Lin, D, Lin, J, Lindstrom, S, Linet, M, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, Mcglynn, Ka, McKean Cowdin, R, Mcneill, Lh, Mcwilliams, Rr, Melin, B, Meltzer, P, Mensah, Je, Miao, X, Michaud, D, Mondul, Am, Moore, Le, Muir, K, Niwa, S, Olson, Sh, Orr, N, Panico, Salvatore, Park, Jy, Patel, Av, Patino Garcia, A, Pavanello, S, Peeters, Ph, Peplonska, B, Peters, U, Petersen, Gm, Picci, P, Pike, Mc, Porru, S, Prescott, J, Pu, X, Purdue, Mp, Qiao, Yl, Rajaraman, P, Riboli, E, Risch, Ha, Rodabough, Rj, Rothman, N, Ruder, Am, Ryu, J, Sanson, M, Schned, A, Schumacher, Fr, Schwartz, Ag, Schwartz, Kl, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, Hd, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, Xo, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, Ad, Silverman, Dt, Simon, M, Southey, Mc, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, Mc, Stevens, Vl, Stolzenberg Solomon, Rz, Stram, Do, Strom, S, Su, Wc, Sund, M, Sung, Sw, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Zz, Tardon, A, Tay, E, Taylor, Pr, Tettey, Y, Thomas, Dm, Tirabosco, R, Tjonneland, A, Tobias, G, Toro, Jr, Travis, Rc, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Yh, Tucker, Ma, Tumino, R, Van Den Berg, D, Van Den Eeden, Sk, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, J, Wang, S, Weiderpass, E, Weinstein, Sj, Wentzensen, N, Wheeler, W, White, E, Wiencke, Jk, Wolk, A, Wolpin, Bm, Wong, Mp, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Yl, Wunder, J, Xiang, Yb, Xu, J, Yang, Hp, Yang, Pc, Yatabe, Y, Ye, Y, Yeboah, Ed, Yin, Z, Ying, C, Yu, Cj, Yu, K, Yuan, Jm, Zanetti, Ka, Zeleniuch Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, Sa, Kraft, P, Chanock, Sj, Yeager, M, Landi, Mt, Shi, J, Chatterjee, N, Amundadottir, Lt, Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C.C., Sampson, J.N., Hoskins, J.W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P.S., Abnet, C.C., Adjei, A.A., Ahlbom, A., Albanes, D., Allen, N.E., Ambrosone, C.B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Gerald Andriole, G.A., Jr., Andrulis, I.L., Arici, C., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Freeman, L.E.B., Berg, C.D., Berndt, S.I., Bertazzi, P.A., Biritwum, R.B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M.-C., Bracci, P.M., Brennan, P., Brinton, L.A., Brotzman, M., Bueno-de-Mesquita, H.B., Buring, J.E., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N.E., Carrato, A., Carreon, T., Carta, A., Chang, G.-C., Chang, I.-S., Chang-Claude, J., Che, X., Chen, C.-J., Chen, C.-Y., Chen, C.-H., Chen, C., Chen, K.-Y., Chen, Y.-M., Chokkalingam, A.P., Chu, L.W., Clavel-Chapelon, F., Colditz, G.A., Colt, J.S., Conti, D., Cook, M.B., Cortessis, V.K., Crawford, E.D., Cussenot, O., Davis, F.G., De Vivo, I., Deng, X., Ding, T., Dinney, C.P., Di Stefano, A.L., Diver, W.R., Duell, E.J., Elena, J.W., Fan, J.-H., Feigelson, H.S., Feychting, M., Figueroa, J.D., Flanagan, A.M., Fraumeni, J.F., Jr., Freedman, N.D., Fridley, B.L., Fuchs, C.S., Gago-Dominguez, M., Gallinger, S., Gao, Y.-T., Gapstur, S.M., Garcia-Closas, M., Garcia-Closas, R., Gastier-Foster, J.M., Gaziano, J.M., Gerhard, D.S., Giffen, C.A., Giles, G.G., Gillanders, E.M., Giovannucci, E.L., Goggins, M., Gokgoz, N., Goldstein, A.M., Gonzalez, C., Gorlick, R., Greene, M.H., Gross, M., Grossman, H.B., Grubb, R., III and Gu, J., Guan, P., Haiman, C.A., Hallmans, G., Hankinson, S.E., Harris, C.C., Hartge, P., Hattinger, C., Hayes, R.B., He, Q., Helman, L., Henderson, B.E., Henriksson, R., Hoffman-Bolton, J., Hohensee, C., Holly, E.A., Hong, Y.-C., Hoover, R.N., Dean Hosgood, H., Hsiao, C.-F., Hsing, A.W., Hsiung, C.A., Hu, N., Hu, W., Hu, Z., Huang, M.-S., Hunter, D.J., Inskip, P.D., Ito, H., Jacobs, E.J., Jacobs, K.B., Jenab, M., Ji, B.-T., Johansen, C., Johansson, M., Johnson, A., Kaaks, R., Kamat, A.M., Kamineni, A., Karagas, M., Khanna, C., Khaw, K.-T., Kim, C., Kim, I.-S., Kim, J.H., Kim, Y.H., Kim, Y.-C., Kim, Y.T., Kang, C.H., Jung, Y.J., Kitahara, C.M., Klein, A.P., Klein, R., Kogevinas, M., Koh, W.-P., Kohno, T., Kolonel, L.N., Kooperberg, C., Kratz, C.P., Krogh, V., Kunitoh, H., Kurtz, R.C., Kurucu, N., Lan, Q., Lathrop, M., Lau, C.C., Lecanda, F., Lee, K.-M., Lee, M.P., Marchand, L.L., Lerner, S.P., Li, D., Liao, L.M., Lim, W.-Y., Lin, D., Lin, J., Lindstrom, S., Linet, M.S., Lissowska, J., Liu, J., Ljungberg, B., Lloreta, J., Lu, D., Ma, J., Malats, N., Mannisto, S., Marina, N., Mastrangelo, G., Matsuo, K., McGlynn, K.A., McKean-Cowdin, R., McNeil, L.H., McWilliams, R.R., Melin, B.S., Meltzer, P.S., Mensah, J.E., Miao, X., Michaud, D.S., Mondul, A.M., Moore, L.E., Muir, K., Niwa, S., Olson, S.H., Orr, N., Panico, S., Park, J.Y., Patel, A.V., Patino-Garcia, A., Pavanello, S., Peeters, P.H.M., Peplonska, B., Peters, U., Petersen, G.M., Picci, P., Pike, M.C., Porru, S., Prescott, J., Pu, X., Purdue, M.P., Qiao, Y.-L., Rajaraman, P., Riboli, E., Risch, H.A., Rodabough, R.J., Rothman, N., Ruder, A.M., Ryu, J.-S., Sanson, M., Schned, A., Schumacher, F.R., Schwartz, A.G., Schwartz, K.L., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H.D., Severi, G., Shen, H., Shen, M., Shete, S., Shiraishi, K., Shu, X.-O., Siddiq, A., Sierrasesumaga, L., Sierri, S., Sihoe, A.D.L., Silverman, D.T., Simon, M., Southey, M.C., Spector, L., Spitz, M., Stampfer, M., Stattin, P., Stern, M.C., Stevens, V.L., Stolzenberg-Solomon, R.Z., Stram, D.O., Strom, S.S., Su, W.-C., Sund, M., Sung, S.W., Swerdlow, A., Tan, W., Tanaka, H., Tang, W., Tang, Z.-Z., Tardon, A., Tay, E., Taylor, P.R., Tettey, Y., Thomas, D.M., Tirabosco, R., Tjonneland, A., Tobias, G.S., Toro, J.R., Travis, R.C., Trichopoulos, D., Troisi, R., Truelove, A., Tsai, Y.-H., Tucker, M.A., Tumino, R., Van Den Berg, D., Van Den Eeden, S.K., Vermeulen, R., Vineis, P., Visvanathan, K., Vogel, U., Wang, C., Wang, J., Wang, S.S., Weiderpass, E., Weinstein, S.J., Wentzensen, N., Wheeler, W., White, E., Wiencke, J.K., Wolk, A., Wolpin, B.M., Wong, M.P., Wrensch, M., Wu, C., Wu, T., Wu, X., Wu, Y.-L., Wunder, J.S., Xiang, Y.-B., Xu, J., Yang, H.P., Yang, P.-C., Yatabe, Y., Ye, Y., Yeboah, E.D., Yin, Z., Ying, C., Yu, C.-J., Yu, K., Yuan, J.-M., Zanetti, K.A., Zeleniuch-Jacquotte, A., Zheng, W., Zhou, B., Mirabello, L., Savage, S.A., Kraft, P., Chanock, S.J., Yeager, M., Landi, M.T., Shi, J., Chatterjee, N., and Amundadottir, L.T.
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Male ,SINGLE-NUCLEOTIDE POLYMORPHISM ,Genome-wide association study ,Epigenesis, Genetic ,Gene Frequency ,Molecular Biology ,Genetics ,Genetics (clinical) ,Neoplasms ,Odds Ratio ,Genome-wide association studies (GWAS) ,Telomerase ,DNA METHYLATION Author Information ,Association Studies Articles ,General Medicine ,PANCREATIC-CANCER ,PROSTATE-CANCER ,Neoplasm Proteins ,POSTMENOPAUSAL BREAST-CANCER ,TERT PROMOTER MUTATIONS ,Gene Expression Regulation, Neoplastic ,2 SUSCEPTIBILITY LOCI ,DNA methylation ,Chromosomes, Human, Pair 5 ,Female ,Risk ,Locus (genetics) ,Single-nucleotide polymorphism ,TERT and CLPTM1L gene ,Biology ,Polymorphism, Single Nucleotide ,LUNG-CANCER ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Allele ,Gene ,Allele frequency ,Alleles ,Genetic association ,chromosome 5p15.33 ,Computational Biology ,Membrane Proteins ,DNA Methylation ,Genetic Loci ,TELOMERE LENGTH ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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- 2014
11. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause
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Jr, Perry, Yh, Hsu, Di, Chasman, Ad, Johnson, Elks C, Albrecht E, Il, Andrulis, Beesley J, Gs, Berenson, Bergmann S, Se, Bojesen, Mk, Bolla, Brown J, Je, Buring, Campbell H, Chang-Claude J, Chenevix-Trench G, Corre T, Fj, Couch, Cox A, Czene K, Adamo Ap, D., Davies G, Ij, Deary, Dennis J, Df, Easton, Eg, Engelhardt, Jg, Eriksson, Esko T, Fasching P, Jd, Figueroa, Flyger H, Fraser A, Garcia-Closas M, Gasparini P, Gieger C, Giles G, Guenel P, Hägg S, Hall P, Hayward C, Hopper J, Ingelsson E, kConFab investigators, Sl, Kardia, Kasiman K, Ja, Knight, Jari Lahti, Da, Lawlor, Pk, Magnusson, Margolin S, Ja, Marsh, Metspalu A, Je, Olson, Ce, Pennell, Polasek O, Rahman I, Pm, Ridker, Robino A, Rudan I, Rudolph A, Salumets A, Mk, Schmidt, Mj, Schoemaker, En, Smith, Ja, Smith, Southey M, Stöckl D, Aj, Swerdlow, Dj, Thompson, Truong T, Ulivi S, Waldenberger M, Wang Q, Wild S, Jf, Wilson, Af, Wright, Zgaga L, ReproGen Consortium, Kk, Ong, Jm, Murabito, Karasik D, Murray A, kConFab investigators, ReproGen Consortium, Perry, Jr, Hsu, Yh, Chasman, Di, Johnson, Ad, Elks, C, Albrecht, E, Andrulis, Il, Beesley, J, Berenson, G, Bergmann, S, Bojesen, Se, Bolla, Mk, Brown, J, Buring, Je, Campbell, H, Chang Claude, J, Chenevix Trench, G, Corre, T, Couch, Fj, Cox, A, Czene, K, D'Adamo, ADAMO PIO, Davies, G, Deary, Ij, Dennis, J, Easton, Df, Engelhardt, Eg, Eriksson, Jg, Esko, T, Fasching, Pa, Figueroa, Jd, Flyger, H, Fraser, A, Garcia Closas, M, Gasparini, Paolo, Gieger, C, Giles, G, Guenel, P, Hägg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kconfab, Investigator, Kardia, Sl, Kasiman, K, Knight, Ja, Lahti, J, Lawlor, Da, Magnusson, Pk, Margolin, S, Marsh, Ja, Metspalu, A, Olson, Je, Pennell, Ce, Polasek, O, Rahman, I, Ridker, Pm, Robino, Antonietta, Rudan, I, Rudolph, A, Salumets, A, Schmidt, Mk, Schoemaker, Mj, Smith, En, Smith, Ja, Southey, M, Stöckl, D, Swerdlow, Aj, Thompson, Dj, Truong, T, Ulivi, S, Waldenberger, M, Wang, Q, Wild, S, Wilson, Jf, Wright, Af, Zgaga, L, Consortium, R, Ong, Kk, Murabito, Jm, Karasik, D, and Murray, A.
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Association Studies Articles ,Age Factors ,Polymorphism, Single Nucleotide ,age at menopause ,GWAS ,MSH6 gene ,DNA-Binding Proteins ,Medizinische Fakultät ,Humans ,Female ,ddc:610 ,Menopause ,Genome-Wide Association Study - Abstract
The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain
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- 2013
12. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
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Rajesh Kumar, Gerald L. Andriole, Robert L. Grubb, Monica McGrath, Amanda Black, Manuela Gago-Dominguez, Margaret A. Knowles, Francisco X. Real, Nilanjan Chatterjee, Thorunn Rafnar, Kevin B. Jacobs, Silvia Polidoro, Debra T. Silverman, Sita H. Vermeulen, Manuel Sanchez, Núria Malats, Salvatore Panico, Amy Hutchinson, William Wheeler, Carmen Navarro, Montserrat Garcia-Closas, Carlotta Sacerdote, Gabriel Valdivia, Yi-Ping Fu, Kari Stefansson, Michelle A.T. Hildebrandt, Alessandra Allione, Katja K.H. Aben, Alison Johnson, W. Ryan Diver, Laurie Burdett, Sophia C.E. Bolick, David J. Hunter, Jarmo Virtamo, Jack A. Taylor, Ludmila Prokunina-Olsson, José I Sanz-Velez, Mark P. Purdue, Fulvio Ricceri, Elio Riboli, Maria Teresa Landi, Susan M. Gapstur, Søren Besenbacher, Joseph F. Fraumeni, Olivier Cussenot, J. Alfred Witjes, Victoria K. Cortessis, Paul Brennan, Tony Fletcher, David Van Den Berg, Börje Ljungberg, Lambertus A. Kiemeney, Dalsu Baris, Mark Teo, Zongli Xu, Geraldine Cancel-Tassin, Holger Dietrich, Zhaoming Wang, Maria D. Garcia-Prats, Françoise Clavel-Chapelon, Adonina Tardón, Paolo Vineis, Peter Rudnai, Margaret R. Karagas, Naomi E. Allen, H. Bas Bueno-de-Mesquita, Molly Schwenn, Jose I. Mayordomo, Ashley C. Godfrey, Manolis Kogevinas, Silvia Selinski, Stephen J. Chanock, Jonine D. Figueroa, Alan R. Schned, Stefano Porru, Mariana C. Stern, Demetrius Albanes, Simonetta Guarrera, Patrick Sulem, Immaculata De Vivo, Hushan Yang, Robert N. Hoover, Kvetoslava Koppova, Michael J. Thun, Malcolm C. Pike, Giuseppe Matullo, D T Bishop, Neil E. Caporaso, Klaus Golka, Eugen Gurzau, Colin P.N. Dinney, Josep Lloreta, Nathaniel Rothman, Eric J. Jacobs, Simone Benhamou, Alfredo Carrato, Federico Canzian, Xifeng Wu, Consol Serra, Anne Tjønneland, Jian-Min Yuan, Meredith Yeager, Reina García-Closas, Stephanie J. Weinstein, Jan G. Hengstler, Dimitrios Trichopoulos, Remco R. R. Makkinje, Anne E. Kiltie, Bogdan Czerniak, Meng Chen, Rothman, N, Garcia Closas, M, Chatterjee, N, Malats, N, Wu, X, Figueroa, Jd, Real, Fx, Van Den Berg, D, Matullo, G, Baris, D, Thun, M, Kiemeney, La, Vineis, P, De Vivo, I, Albanes, D, Purdue, Mp, Rafnar, T, Hildebrandt, Ma, Kiltie, Ae, Cussenot, O, Golka, K, Kumar, R, Taylor, Ja, Mayordomo, Ji, Jacobs, Kb, Kogevinas, M, Hutchinson, A, Wang, Z, Fu, Yp, Prokunina Olsson, L, Burdett, L, Yeager, M, Wheeler, W, Tardón, A, Serra, C, Carrato, A, García Closas, R, Lloreta, J, Johnson, A, Schwenn, M, Karagas, Mr, Schned, A, Andriole G., Jr, Grubb R., 3rd, Black, A, Jacobs, Ej, Diver, Wr, Gapstur, Sm, Weinstein, Sj, Virtamo, J, Cortessis, Vk, Gago Dominguez, M, Pike, Mc, Stern, Mc, Yuan, Jm, Hunter, Dj, Mcgrath, M, Dinney, Cp, Czerniak, B, Chen, M, Yang, H, Vermeulen, Sh, Aben, Kk, Witjes, Ja, Makkinje, Rr, Sulem, P, Besenbacher, S, Stefansson, K, Riboli, E, Brennan, P, Panico, Salvatore, Navarro, C, Allen, Ne, Bueno de Mesquita, Hb, Trichopoulos, D, Caporaso, Nicola, Landi, Mt, Canzian, F, Ljungberg, B, Tjonneland, A, Clavel Chapelon, F, Bishop, Dt, Teo, Mt, Knowles, Ma, Guarrera, S, Polidoro, S, Ricceri, F, Sacerdote, C, Allione, A, Cancel Tassin, G, Selinski, S, Hengstler, Jg, Dietrich, H, Fletcher, T, Rudnai, P, Gurzau, E, Koppova, K, Bolick, Sc, Godfrey, A, Xu, Z, Sanz Velez, Ji, D., García Prats M, Sanchez, M, Valdivia, G, Porru, S, Benhamou, S, Hoover, Rn, Fraumeni JF, Jr, Silverman, Dt, and Chanock, Sj
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Male ,Arylamine N-Acetyltransferase ,Chromosomes, Human, Pair 22 ,Genome-wide association study ,Aetiology, screening and detection [ONCOL 5] ,medicine.disease_cause ,Genome-wide association studies ,Risk Factors ,genome-wide association ,bladder cancer ,Psychology ,Genetics ,Sex Characteristics ,Incidence ,Bladder cancer ,Smoking ,Chromosome Mapping ,Single Nucleotide ,Tag SNP ,Europe ,Chromosomes, Human, Pair 2 ,Pair 2 ,Female ,Human ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Risk Assessment ,Chromosomes ,Article ,Molecular epidemiology [NCEBP 1] ,Translational research [ONCOL 3] ,medicine ,Humans ,Family ,Genetic Predisposition to Disease ,Polymorphism ,Pair 18 ,Pair 22 ,Genome-Wide Association Study ,Neoplasm Staging ,Spain ,United States ,Urinary Bladder Neoplasms ,Cancer ,Chromosome ,medicine.disease ,Evaluation of complex medical interventions [NCEBP 2] ,Carcinogenesis ,Chromosomes, Human, Pair 18 - Abstract
We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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- 2010
13. Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
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Davidson AL, Michailidou K, Parsons MT, Fortuno C, Bolla MK, Wang Q, Dennis J, Naven M, Abubakar M, Ahearn TU, Alonso MR, Andrulis IL, Antoniou AC, Auvinen P, Behrens S, Bermisheva MA, Bogdanova NV, Bojesen SE, Brüning T, Byers HJ, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Collée JM, Czene K, Dörk T, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Gronwald J, Guénel P, Hadjisavvas A, Haeberle L, Hall P, Hamann U, Hartman M, Ho PJ, Hooning MJ, Hoppe R, Howell A, Jakubowska A, Khusnutdinova EK, Kristensen VN, Li J, Lim J, Lindblom A, Liu J, Lophatananon A, Mannermaa A, Mavroudis DA, Mensenkamp AR, Milne RL, Muir KR, Newman WG, Obi N, Panayiotidis MI, Park SK, Park-Simon TW, Peterlongo P, Radice P, Rashid MU, Rhenius V, Saloustros E, Sawyer EJ, Schmidt MK, Seibold P, Shah M, Southey MC, Teo SH, Tomlinson I, Torres D, Truong T, van de Beek I, van der Hout AH, Wendt CC, Dunning AM, Pharoah PDP, Devilee P, Easton DF, James PA, and Spurdle AB
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- Humans, Female, BRCA2 Protein genetics, BRCA1 Protein genetics, Fanconi Anemia Complementation Group N Protein genetics, Middle Aged, Mutation, Missense genetics, Adult, Tumor Suppressor Protein p53 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation genetics
- Abstract
Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels., Competing Interests: Declaration of interests P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of VUSs in BRCA1 and BRCA2. The funds were paid to the institution., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2024
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14. Contribution of pre-diagnostic host factors to shaping the stromal microenvironment of breast cancer among sub-Saharan African women.
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Abubakar M, Ahearn TU, Duggan MA, Lawrence S, Adjei EK, Clegg-Lamptey JN, Yarney J, Wiafe-Addai B, Awuah B, Wiafe S, Nyarko K, Aitpillah FS, Ansong D, Hewitt SM, Brinton LA, Figueroa JD, Garcia-Closas M, Edusei L, and Titiloye N
- Abstract
Background: The stromal microenvironment (SME) is integral to breast cancer (BC) biology, impacting metastatic proclivity and treatment response. Emerging data indicate that host factors may impact the SME, but the relationship between pre-diagnostic host factors and SME phenotype remains poorly characterized, particularly among women of African ancestry., Methods: We conducted a case-only analysis involving 792 BC patients (17-84 years) from the Ghana Breast Health Study (GBHS). High-accuracy machine-learning algorithms were applied to standard H&E-stained images to characterize SME phenotypes (including percent tumor-associated connective tissue stroma, Ta-CTS (%), and tumor-associated stromal cellular density, Ta-SCD (%)). Associations between pre-diagnostic host factors and SME phenotypes were assessed in multivariable linear regression models., Results: Decreasing Ta-CTS and increasing Ta-SCD were associated with aggressive, mostly high-grade tumors (p-value<0.001). Several pre-diagnostic host factors were associated with Ta-SCD independently of tumor characteristics. Compared with nulliparous women, parous women had higher levels of Ta-SCD [mean (standard deviation, SD) = 31.3% (7.6%) vs. 28.9% (7.1%); p-value=0.01]. Similarly, women with a positive family history of breast cancer had higher levels of Ta-SCD than those without family history [mean (SD) = 33.0% (7.5%)] vs. 30.9% (7.6%); p-value=0.03]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (SD) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, average, and large body sizes, respectively, p-value=0.005]., Conclusions: Epidemiological risk factors were associated with varying degrees of stromal cellularity in tumors, independently of clinicopathological characteristics., Impact: The findings raise the possibility that epidemiological risk factors may partly influence tumor biology via the SME.
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- 2024
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15. Early life adversity impacts alterations in brain structure and food addiction in individuals with high BMI.
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Ravichandran S, Sood R, Das I, Dong T, Figueroa JD, Yang J, Finger N, Vaughan A, Vora P, Selvaraj K, Labus JS, and Gupta A
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- Humans, Female, Male, Adult, Adverse Childhood Experiences psychology, Reward, Young Adult, Middle Aged, Surveys and Questionnaires, Resilience, Psychological, Body Mass Index, Food Addiction psychology, Brain diagnostic imaging, Brain pathology, Brain physiopathology, Magnetic Resonance Imaging, Obesity psychology, Obesity pathology
- Abstract
Obesity and food addiction are associated with distinct brain signatures related to reward processing, and early life adversity (ELA) also increases alterations in these same reward regions. However, the neural mechanisms underlying the effect of early life adversity on food addiction are unknown. Therefore, the aim of this study was to examine the interactions between ELA, food addiction, and brain morphometry in individuals with obesity. 114 participants with high body mass index (BMI) underwent structural MRIs, and completed several questionnaires (e.g., Yale Food Addiction Scale (YFAS), Brief Resilience Scale (BRS), Early Traumatic Inventory (ETI)). Freesurfer 6 was applied to generate the morphometry of brain regions. A multivariate pattern analysis was used to derive brain morphometry patterns associated with food addiction. General linear modeling and mediation analyses were conducted to examine the effects of ELA and resilience on food addiction in individuals with obesity. Statistical significance was determined at a level of p < 0.05. High levels of ELA showed a strong association between reward control brain signatures and food addiction (p = 0.03). Resilience positively mediated the effect of ELA on food addiction (B = 0.02, p = 0.038). Our findings suggest that food addiction is associated with brain signatures in motivation and reward processing regions indicative of dopaminergic dysregulation and inhibition of cognitive control regions. These mechanistic variabilities along with early life adversity suggest increased vulnerability to develop food addiction and obesity in adulthood, which can buffer by the neuroprotective effects of resilience, highlighting the value of incorporating cognitive appraisal into obesity therapeutic regimens., (© 2024. The Author(s).)
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- 2024
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16. Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.
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Sharafeddin F, Sierra J, Ghaly M, Simon TB, Ontiveros-Ángel P, Edelbach B, Febo M, Labus J, and Figueroa JD
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- Animals, Male, Rats, Behavior, Animal physiology, Reflex, Startle physiology, Female, ADAM17 Protein metabolism, Prefrontal Cortex metabolism, Rats, Inbred Lew, Stress, Psychological physiopathology, Stress, Psychological metabolism
- Abstract
Introduction: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses., Methods: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma., Results: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle)., Conclusion: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)
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- 2024
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17. Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.
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Mullooly M, Fan S, Pfeiffer RM, Bowles EA, Duggan MA, Falk RT, Richert-Boe K, Glass AG, Kimes TM, Figueroa JD, Rohan TE, Abubakar M, and Gierach GL
- Subjects
- Female, Humans, Breast Density, Case-Control Studies, Risk Factors, Breast Neoplasms etiology, Breast Diseases complications
- Abstract
Introduction: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD., Methods: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression., Results: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99)., Discussion: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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18. The enzymes of the oxidative phase of the pentose phosphate pathway as targets of reactive species: consequences for NADPH production.
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Fuentes-Lemus E, Reyes JS, Figueroa JD, Davies MJ, and López-Alarcón C
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- NADP chemistry, NADP metabolism, Oxidation-Reduction, Oxidants, Pentose Phosphate Pathway physiology, Oxidative Stress
- Abstract
The pentose phosphate pathway (PPP) is a key metabolic pathway. The oxidative phase of this process involves three reactions catalyzed by glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL) and 6-phosphogluconate dehydrogenase (6PGDH) enzymes. The first and third steps (catalyzed by G6PDH and 6PGDH, respectively) are responsible for generating reduced nicotinamide adenine dinucleotide phosphate (NAPDH), a key cofactor for maintaining the reducing power of cells and detoxification of both endogenous and exogenous oxidants and electrophiles. Despite the importance of these enzymes, little attention has been paid to the fact that these proteins are targets of oxidants. In response to oxidative stimuli metabolic pathways are modulated, with the PPP often up-regulated in order to enhance or maintain the reductive capacity of cells. Under such circumstances, oxidation and inactivation of the PPP enzymes could be detrimental. Damage to the PPP enzymes may result in a downward spiral, as depending on the extent and sites of modification, these alterations may result in a loss of enzymatic activity and therefore increased oxidative damage due to NADPH depletion. In recent years, it has become evident that the three enzymes of the oxidative phase of the PPP have different susceptibilities to inactivation on exposure to different oxidants. In this review, we discuss existing knowledge on the role that these enzymes play in the metabolism of cells, and their susceptibility to oxidation and inactivation with special emphasis on NADPH production. Perspectives on achieving a better understanding of the molecular basis of the oxidation these enzymes within cellular environments are given., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2023
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19. Mosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study.
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Olivos N, Banta JE, Spencer-Hwang R, Ansong D, Beane Freeman LE, Clegg-Lamptey JN, Wiafe-Addai B, Edusei L, Adjei E, Titiloye N, Dedey F, Aitpillah F, Oppong J, Vanderpuye V, Osei-Bonsu E, Ahearn TU, Biritwum R, Yarney J, Awuah B, Nyarko K, Garcia-Closas M, Abubakar M, Brinton LA, Figueroa JD, and Wiafe S
- Subjects
- Animals, Humans, Female, Mosquito Control, Ghana epidemiology, Insecticides adverse effects, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Breast Neoplasms prevention & control, Malaria prevention & control, Insect Repellents adverse effects
- Abstract
Epidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 controls from the Ghana Breast Health Study conducted from 2013 to 2015, we investigated associations with mosquito control products to reduce the spread of mosquito-borne diseases, such as malaria. These mosquito control products were insecticide-treated nets, mosquito coils, repellent room sprays, and skin creams for personal protection against mosquitos. Multivariable and polytomous logistic regression models were used to estimate odds ratios (OR
adj ) and 95% confidence intervals (CI) with breast cancer risk-adjusted for potential confounders and known risk factors. Among controls, the reported use of mosquito control products were mosquito coils (65%), followed by insecticide-treated nets (56%), repellent room sprays (53%), and repellent skin creams (15%). Compared to a referent group of participants unexposed to mosquito control products, there was no significant association between breast cancer risk and mosquito coils. There was an association in breast cancer risk with reported use of insecticide-treated nets; however, that association was weak and not statistically significant. Participants who reported using repellent sprays were at elevated risks compared to women who did not use any mosquito control products, even after adjustment for all other mosquito control products (OR = 1.42, 95% CI=1.15-1.75). We had limited power to detect an association with repellent skin creams. Although only a few participants reported using repellent room sprays weekly/daily or < month-monthly, no trends were evident with increased frequency of use of repellent sprays, and there was no statistical evidence of heterogeneity by estrogen receptor (ER) status (p-het > 0.25). Our analysis was limited when determining if an association existed with repellent skin creams; therefore, we cannot conclude an association. We found limited evidence of risk associations with widely used mosquito coils and insecticide-treated nets, which are reassuring given their importance for malaria prevention. Our findings regarding specific breast cancer risk associations, specifically those observed between repellent sprays, require further study., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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20. Antioxidant Capacity of Free and Peptide Tryptophan Residues Determined by the ORAC (Oxygen Radical Absorbance Capacity) Assay Is Modulated by Radical-Radical Reactions and Oxidation Products.
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Figueroa JD, Barroso-Torres N, Morales M, Herrera B, Aranda M, Dorta E, and López-Alarcón C
- Abstract
The ORAC (Oxygen Radical Absorbance Capacity) assay is commonly employed for determining the antioxidant capacity of bioactive peptides. To gain insights into the meaning of this index for peptides containing a single Trp, we studied the consumption of this residue and fluorescein (FLH, the probe of ORAC method), induced by radicals generated by AAPH (2,2'-Azo-bis(2-amidinopropane) dihydrochloride) thermolysis. ORAC values were rationalized from kinetics and computational calculations of bond dissociation energies (BDE) of the N-H bond (indole ring of Trp). Free Trp, di- and tri- peptides, and three larger peptides were studied. Solutions containing 70 nM FLH, 1-5 μM free Trp or peptides, and 10 mM AAPH were incubated at 37 °C in phosphate buffer. Kinetic studies showed that FLH minimally affected Trp consumption. However, a clear protection of FLH, characterized by pseudo-lag times, was evidenced, reflecting radical-radical reactions and FLH repairing. Peptides showed similar ORAC values (~1.9-2.8 Trolox equivalents), while BDE varied between 91.9 and 103.5 kcal. These results, added to the protection of FLH observed after total consumption of Trp, indicate a lack of discrimination of the assay for the chemical structure of peptides and the contribution of oxidation products to the index.
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- 2023
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21. Cardiovascular events and venous thromboembolism after primary malignant or non-malignant brain tumour diagnosis: a population matched cohort study in Wales (United Kingdom).
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Poon MTC, Brennan PM, Jin K, Sudlow CLM, and Figueroa JD
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- Adult, Humans, Cohort Studies, Wales epidemiology, Risk Factors, United Kingdom epidemiology, Venous Thromboembolism diagnosis, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Stroke complications, Brain Neoplasms diagnosis, Brain Neoplasms epidemiology
- Abstract
Background: Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the CVD incidences and cardiovascular risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities., Methods: Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥ 18 years in the primary care database with first diagnosis of malignant or non-malignant brain tumour identified in the cancer registry in 2000-2014 and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any cancer diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour (malignant or non-malignant) and follow-up period., Results: There were 2869 and 3931 people diagnosed with malignant or non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). After the first year, the risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) remained higher than controls. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls., Conclusions: The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour., (© 2023. The Author(s).)
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- 2023
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22. Population-specific Mutation Patterns in Breast Tumors from African American, European American, and Kenyan Patients.
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Tang W, Zhang F, Byun JS, Dorsey TH, Yfantis HG, Ajao A, Liu H, Pichardo MS, Pichardo CM, Harris AR, Yang XR, Figueroa JD, Sayed S, Makokha FW, and Ambs S
- Subjects
- Female, Humans, F-Box-WD Repeat-Containing Protein 7 genetics, Kenya, Mutation, United States, White genetics, Black People genetics, Asian genetics, Black or African American genetics, Breast Neoplasms genetics
- Abstract
Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer., Significance: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients., (© 2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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23. Evaluation of the association of area-level socioeconomic deprivation and breast cancer recurrence by oestrogen receptor subtypes in Scotland.
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Dunlop HM, Williams LJ, Hall PS, Barber M, Dodds C, and Figueroa JD
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- Humans, Female, Receptors, Estrogen, Mastectomy, Breast pathology, Socioeconomic Factors, Breast Neoplasms pathology
- Abstract
Background: Women from socioeconomically deprived areas have lower breast cancer (BC) incidence rates for screen-detected oestrogen receptor (ER) + tumours and higher mortality for select tumour subtypes. We aimed to determine if ipsilateral breast cancer recurrence (IBR) differs by Scottish Index of Multiple Deprivation (SIMD) quintile and tumour subtype in Scotland., Methods: Patient data for primary invasive BC diagnosed in 2007-2008 in Scotland was analysed. Manual case-note review for 3495 patients from 10 years post-diagnosis was used. To determine the probability of IBR while accounting for the competing risk of death from any cause, cumulative incidence functions stratified by ER subtype and surgery were plotted. Multivariable Cox Proportional Hazards models were used to estimate the association of SIMD accounting for other predictors of IBR., Results: Among 2819 ER + tumours, 423 patients had a recurrence and 438 died. SIMD was related to death (p = 0.018) with the most deprived more likely to have died in the 10-year period (17.7% vs. 12.9%). We found no significant differences by SIMD in prognostic tumour characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumours, 105 died and 185 had a recurrence. We found no significant differences in prognostic tumour characteristics by SIMD except screen detection with the most deprived more likely than the least to have their tumours detected from screening (46.9% vs. 28%, p = 0.03). Among patients with ER- tumours, 50% had mastectomy and the most deprived had increased 5-year IBR risk compared to the least deprived (HR 3.03 [1.41-6.53])., Conclusions: IBR is not a major contributor to mortality differences by SIMD for the majority of BC patients in our study. The lack of inequities in IBR are likely due to standardised treatment protocols and access to healthcare. The association with socioeconomic deprivation and recurrence for ER- tumours requires further study., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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24. Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.
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Wichert K, Hoppe R, Ickstadt K, Behrens T, Winter S, Herold R, Terschüren C, Lo WY, Guénel P, Truong T, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Andrulis IL, Brenner H, Chang-Claude J, Cox A, Cross SS, Czene K, Eriksson M, Figueroa JD, García-Closas M, Goldberg MS, Hamann U, He W, Holleczek B, Hopper JL, Jakubowska A, Ko YD, Lubiński J, Mulligan AM, Obi N, Rhenius V, Shah M, Shu XO, Simard J, Southey MC, Zheng W, Dunning AM, Pharoah PDP, Hall P, Easton DF, Brüning T, Brauch H, Harth V, and Rabstein S
- Subjects
- Humans, Female, Bayes Theorem, Polymorphism, Single Nucleotide, Logistic Models, Case-Control Studies, Genetic Predisposition to Disease, Breast Neoplasms genetics, Breast Neoplasms epidemiology, Melatonin genetics, Melatonin metabolism
- Abstract
Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483
R ∧ rs1473473D ∧ rs3729931D : OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation., (© 2023. The Author(s).)- Published
- 2023
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25. Cancer referrals at African Inland Church Kijabe Hospital, Kiambu County (2014-2020) and the impact of COVID-19.
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Kamita M, Bird P, Akinyi B, Kamau RW, Carter R, Muma S, Adam M, Makori T, Figueroa JD, and Makokha F
- Subjects
- Male, Female, Humans, Kenya epidemiology, Pandemics, Retrospective Studies, Cross-Sectional Studies, Hospitals, Referral and Consultation, COVID-19, Neoplasms epidemiology
- Abstract
In Kenya, cancer is the third leading cause of death. The African Inland Church Kijabe Hospital (AICKH) is a level 4 missionary hospital. The hospital serves the Kenyan population in many areas, including cancer care, and some of these services were affected during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to leverage a recently established hospital-based cancer registry of patients treated at AICKH between 2014 and 2020 to describe the cancer cases and patient referral patterns seen at AICKH during the COVID-19 pandemic in 2020. A cross-sectional retrospective survey was conducted through medical records abstraction in the surgery, breast clinic, palliative care and pathology departments. A total of 3279 cases were included in the study, with females accounting for 58.1% of the cases. The top-three cancers overall were breast (23.0%), oesophagus (20.5%) and prostate (8.6%). There was a minimal increase in the number of cancer cases in 2020 (1.7%) compared with 2019, with an increase of 19.3% in 2019 compared with 2018. In conclusion, AICKH is one of the few hospitals in Kenya where a large number of cancer patients seek healthcare, and referral of cancer cases changed in 2020, which may be due to the COVID-19 pandemic. Future efforts can leverage this registry to determine the impacts of cancer diagnosis and treatment on survival outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)
- Published
- 2023
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26. Associations of Circulating Estrogens and Estrogen Metabolites with Fecal and Oral Microbiome in Postmenopausal Women in the Ghana Breast Health Study.
- Author
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Wu Z, Pfeiffer RM, Byrd DA, Wan Y, Ansong D, Clegg-Lamptey JN, Wiafe-Addai B, Edusei L, Adjei E, Titiloye N, Dedey F, Aitpillah F, Oppong J, Vanderpuye V, Osei-Bonsu E, Dagnall CL, Jones K, Hutchinson A, Hicks BD, Ahearn TU, Knight R, Biritwum R, Yarney J, Wiafe S, Awuah B, Nyarko K, Garcia-Closas M, Sinha R, Figueroa JD, Brinton LA, Trabert B, and Vogtmann E
- Subjects
- Female, Humans, Estrogens urine, Postmenopause physiology, RNA, Ribosomal, 16S genetics, Ghana epidemiology, Breast Neoplasms epidemiology, Breast Neoplasms urine, Microbiota, Lactobacillales metabolism
- Abstract
The human fecal and oral microbiome may play a role in the etiology of breast cancer through modulation of endogenous estrogen metabolism. This study aimed to investigate associations of circulating estrogens and estrogen metabolites with the fecal and oral microbiome in postmenopausal African women. A total of 117 women with fecal (N = 110) and oral (N = 114) microbiome data measured by 16S rRNA gene sequencing, and estrogens and estrogen metabolites data measured by liquid chromatography tandem mass spectrometry were included. The outcomes were measures of the microbiome and the independent variables were the estrogens and estrogen metabolites. Estrogens and estrogen metabolites were associated with the fecal microbial Shannon index (global P < 0.01). In particular, higher levels of estrone (β = 0.36, P = 0.03), 2-hydroxyestradiol (β = 0.30, P = 0.02), 4-methoxyestrone (β = 0.51, P = 0.01), and estriol (β = 0.36, P = 0.04) were associated with higher levels of the Shannon index, while 16alpha-hydroxyestrone (β = -0.57, P < 0.01) was inversely associated with the Shannon index as indicated by linear regression. Conjugated 2-methoxyestrone was associated with oral microbial unweighted UniFrac as indicated by MiRKAT ( P < 0.01) and PERMANOVA, where conjugated 2-methoxyestrone explained 2.67% of the oral microbial variability, but no other estrogens or estrogen metabolites were associated with any other beta diversity measures. The presence and abundance of multiple fecal and oral genera, such as fecal genera from families Lachnospiraceae and Ruminococcaceae , were associated with several estrogens and estrogen metabolites as indicated by zero-inflated negative binomial regression. Overall, we found several associations of specific estrogens and estrogen metabolites and the fecal and oral microbiome. IMPORTANCE Several epidemiologic studies have found associations of urinary estrogens and estrogen metabolites with the fecal microbiome. However, urinary estrogen concentrations are not strongly correlated with serum estrogens, a known risk factor for breast cancer. To better understand whether the human fecal and oral microbiome were associated with breast cancer risk via the regulation of estrogen metabolism, we conducted this study to investigate the associations of circulating estrogens and estrogen metabolites with the fecal and oral microbiome in postmenopausal African women. We found several associations of parent estrogens and several estrogen metabolites with the microbial communities, and multiple individual associations of estrogens and estrogen metabolites with the presence and abundance of multiple fecal and oral genera, such as fecal genera from families Lachnospiraceae and Ruminococcaceae, which have estrogen metabolizing properties. Future large, longitudinal studies to investigate the dynamic changes of the fecal and oral microbiome and estrogen relationship are needed., Competing Interests: The authors declare no conflict of interest.
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- 2023
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27. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry.
- Author
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Middha P, Wang X, Behrens S, Bolla MK, Wang Q, Dennis J, Michailidou K, Ahearn TU, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Augustinsson A, Baert T, Freeman LEB, Becher H, Beckmann MW, Benitez J, Bojesen SE, Brauch H, Brenner H, Brooks-Wilson A, Campa D, Canzian F, Carracedo A, Castelao JE, Chanock SJ, Chenevix-Trench G, Cordina-Duverger E, Couch FJ, Cox A, Cross SS, Czene K, Dossus L, Dugué PA, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Fletcher O, Flyger H, Gabrielson M, Gago-Dominguez M, Giles GG, González-Neira A, Grassmann F, Grundy A, Guénel P, Haiman CA, Håkansson N, Hall P, Hamann U, Hankinson SE, Harkness EF, Holleczek B, Hoppe R, Hopper JL, Houlston RS, Howell A, Hunter DJ, Ingvar C, Isaksson K, Jernström H, John EM, Jones ME, Kaaks R, Keeman R, Kitahara CM, Ko YD, Koutros S, Kurian AW, Lacey JV, Lambrechts D, Larson NL, Larsson S, Le Marchand L, Lejbkowicz F, Li S, Linet M, Lissowska J, Martinez ME, Maurer T, Mulligan AM, Mulot C, Murphy RA, Newman WG, Nielsen SF, Nordestgaard BG, Norman A, O'Brien KM, Olson JE, Patel AV, Prentice R, Rees-Punia E, Rennert G, Rhenius V, Ruddy KJ, Sandler DP, Scott CG, Shah M, Shu XO, Smeets A, Southey MC, Stone J, Tamimi RM, Taylor JA, Teras LR, Tomczyk K, Troester MA, Truong T, Vachon CM, Wang SS, Weinberg CR, Wildiers H, Willett W, Winham SJ, Wolk A, Yang XR, Zamora MP, Zheng W, Ziogas A, Dunning AM, Pharoah PDP, García-Closas M, Schmidt MK, Kraft P, Milne RL, Lindström S, Easton DF, and Chang-Claude J
- Subjects
- Adult, Female, Humans, Genetic Predisposition to Disease, Bayes Theorem, Genome-Wide Association Study, Risk Factors, Polymorphism, Single Nucleotide, Case-Control Studies, Gene-Environment Interaction, Breast Neoplasms etiology, Breast Neoplasms genetics
- Abstract
Background: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer., Methods: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs., Results: Assuming a 1 × 10
-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94)., Conclusions: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)- Published
- 2023
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28. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.
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Morra A, Schreurs MAC, Andrulis IL, Anton-Culver H, Augustinsson A, Beckmann MW, Behrens S, Bojesen SE, Bolla MK, Brauch H, Broeks A, Buys SS, Camp NJ, Castelao JE, Cessna MH, Chang-Claude J, Chung WK, Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Dennis J, Devilee P, Dörk T, Dunning AM, Dwek M, Easton DF, Eccles DM, Eriksson M, Evans DG, Fasching PA, Fehm TN, Figueroa JD, Flyger H, Gabrielson M, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Genkinger J, Grassmann F, Gündert M, Hahnen E, Haiman CA, Hamann U, Harrington PA, Hartikainen JM, Hoppe R, Hopper JL, Houlston RS, Howell A, Jakubowska A, Janni W, Jernström H, John EM, Johnson N, Jones ME, Kristensen VN, Kurian AW, Lambrechts D, Le Marchand L, Lindblom A, Lubiński J, Lux MP, Mannermaa A, Mavroudis D, Mulligan AM, Muranen TA, Nevanlinna H, Nevelsteen I, Neven P, Newman WG, Obi N, Offit K, Olshan AF, Park-Simon TW, Patel AV, Peterlongo P, Phillips KA, Plaseska-Karanfilska D, Polley EC, Presneau N, Pylkäs K, Rack B, Radice P, Rashid MU, Rhenius V, Robson M, Romero A, Saloustros E, Sawyer EJ, Schmutzler RK, Schuetze S, Scott C, Shah M, Smichkoska S, Southey MC, Tapper WJ, Teras LR, Tollenaar RAEM, Tomczyk K, Tomlinson I, Troester MA, Vachon CM, van Veen EM, Wang Q, Wendt C, Wildiers H, Winqvist R, Ziogas A, Hall P, Pharoah PDP, Adank MA, Hollestelle A, Schmidt MK, and Hooning MJ
- Subjects
- Female, Humans, Checkpoint Kinase 2 genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Proportional Hazards Models, Breast Neoplasms genetics, Breast Neoplasms radiotherapy
- Abstract
Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers., Aim: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS., Methods: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death., Results: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]., Conclusion: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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29. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.
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Figlioli G, Billaud A, Ahearn TU, Antonenkova NN, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Blok MJ, Bogdanova NV, Bonanni B, Burwinkel B, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chanock SJ, Czene K, Devilee P, Dörk T, Engel C, Eriksson M, Fasching PA, Figueroa JD, Gabrielson M, Gago-Dominguez M, García-Closas M, González-Neira A, Grassmann F, Guénel P, Gündert M, Hadjisavvas A, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Hillemanns P, Hollestelle A, Hooning MJ, Hoppe R, Howell A, Humphreys K, Jager A, Jakubowska A, Khusnutdinova EK, Ko YD, Kristensen VN, Lindblom A, Lissowska J, Lubiński J, Mannermaa A, Manoukian S, Margolin S, Mavroudis D, Newman WG, Obi N, Panayiotidis MI, Rashid MU, Rhenius V, Rookus MA, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Sironen R, Southey MC, Suvanto M, Tollenaar RAEM, Tomlinson I, Truong T, van der Kolk LE, van Veen EM, Wappenschmidt B, Yang XR, Bolla MK, Dennis J, Dunning AM, Easton DF, Lush M, Michailidou K, Pharoah PDP, Wang Q, Adank MA, Schmidt MK, Andrulis IL, Chang-Claude J, Nevanlinna H, Chenevix-Trench G, Evans DG, Milne RL, Radice P, and Peterlongo P
- Subjects
- Humans, Female, Triple Negative Breast Neoplasms genetics, Genetic Predisposition to Disease, Breast Neoplasms genetics, DNA Helicases genetics
- Abstract
Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs., (© 2023. The Author(s).)
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- 2023
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30. Adaptive immune receptor features related to breast cancer tissue in Kenyan patients: high immunoglobulin gene expression and high levels of gamma-delta T-cells.
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Mwangi KW, Kamita MK, Waweru JW, Sayed S, Figueroa JD, Ambs S, Cios KJ, Blanck G, and Makokha FW
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- Humans, Female, Kenya epidemiology, Genes, Immunoglobulin, Receptors, Antigen, T-Cell genetics, T-Lymphocytes, Breast Neoplasms genetics, Breast Neoplasms therapy
- Abstract
Background: Characterization of the breast cancer (BC) immune response may provide information for a point of intervention, such as application of immunotherapeutic treatments. In this study, we sought to recover and characterize the adaptive immune receptor (IR) recombination reads from genomics files representing Kenyan patients, to better understand the immune response specifically related to those patients., Methods: We used a previously applied algorithm and software to obtain productive IR recombination reads from cancer and adjacent normal tissue samples representing 22 Kenyan BC patients., Results: From both the RNAseq and exome files, there were significantly more T-cell receptor (TCR) recombination reads recovered from tumor samples compared to marginal tissue samples. Also, the immunoglobulin (IG) genes were expressed at a much higher level than the TCR genes (p-value = 0.0183) in the tumor samples. And, the tumor IG CDR3s consistently represented more positively charged amino acid R-groups, in comparison to the marginal tissue, IG CDR3s., Conclusion: For Kenyan patients, a high level of IG expression, representing specific CDR3 chemistries, was associated with BC. These results lay the foundation for studies that could support specific immunotherapeutic interventions for Kenyan BC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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31. Associations of breast cancer etiologic factors with stromal microenvironment of primary invasive breast cancers in the Ghana Breast Health Study.
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Abubakar M, Ahearn TU, Duggan MA, Lawrence S, Adjei E, Clegg-Lamptey JN, Yarney J, Wiafe-Addai B, Awuah B, Wiafe S, Nyarko K, Aitpillah F, Ansong D, Hewitt SM, Brinton LA, Figueroa JD, Garcia-Closas M, Edusei L, and Titiloye N
- Abstract
Background: Emerging data suggest that beyond the neoplastic parenchyma, the stromal microenvironment (SME) impacts tumor biology, including aggressiveness, metastatic potential, and response to treatment. However, the epidemiological determinants of SME biology remain poorly understood, more so among women of African ancestry who are disproportionately affected by aggressive breast cancer phenotypes., Methods: Within the Ghana Breast Health Study, a population-based case-control study in Ghana, we applied high-accuracy machine-learning algorithms to characterize biologically-relevant SME phenotypes, including tumor-stroma ratio (TSR (%); a metric of connective tissue stroma to tumor ratio) and tumor-associated stromal cellular density (Ta-SCD (%); a tissue biomarker that is reminiscent of chronic inflammation and wound repair response in breast cancer), on digitized H&E-stained sections from 792 breast cancer patients aged 17-84 years. Kruskal-Wallis tests and multivariable linear regression models were used to test associations between established breast cancer risk factors, tumor characteristics, and SME phenotypes., Results: Decreasing TSR and increasing Ta-SCD were strongly associated with aggressive, mostly high grade tumors ( p-value < 0.001). Several etiologic factors were associated with Ta-SCD, but not TSR. Compared with nulliparous women [mean (standard deviation) = 28.9% (7.1%)], parous women [mean (standard deviation) = 31.3% (7.6%)] had statistically significantly higher levels of Ta-SCD ( p-value = 0.01). Similarly, women with a positive family history of breast cancer [FHBC; mean (standard deviation) = 33.0% (7.5%)] had higher levels of Ta-SCD than those with no FHBC [mean (standard deviation) = 30.9% (7.6%); p-value = 0.01]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (standard deviation) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, moderate, and large body sizes, respectively, p-value = 0.005]. These associations persisted and remained statistically significantly associated with Ta-SCD in mutually-adjusted multivariable linear regression models ( p-value < 0.05). With the exception of body size, which was differentially associated with Ta-SCD by grade levels ( p-heterogeneity = 0.04), associations between risk factors and Ta-SCD were not modified by tumor characteristics., Conclusions: Our findings raise the possibility that epidemiological factors may act via the SME to impact both risk and biology of breast cancers in this population, underscoring the need for more population-based research into the role of SME in multi-state breast carcinogenesis., Competing Interests: Competing interest The authors declare that they have no competing interests.
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- 2023
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32. The Scottish COVID Cancer Immunity Prevalence Study: A Longitudinal Study of SARS-CoV-2 Immune Response in Patients Receiving Anti-Cancer Treatment.
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Purshouse K, Thomson JP, Vallet M, Alexander L, Bonisteel I, Brennan M, Cameron DA, Figueroa JD, Furrie E, Haig P, Heck M, McCaughan H, Mitchell P, McVicars H, Primrose L, Silva I, Templeton K, Wilson N, and Hall PS
- Subjects
- Humans, SARS-CoV-2, COVID-19 Vaccines, Cross-Sectional Studies, Longitudinal Studies, Pandemics, Immunity, Scotland epidemiology, Vaccination, COVID-19 epidemiology, Neoplasms drug therapy, Neoplasms epidemiology
- Abstract
Background: Cancer and anti-cancer treatment (ACT) may be risk factors for severe SARS-CoV-2 infection and limited vaccine efficacy. Long-term longitudinal studies are needed to evaluate these risks. The Scottish COVID cancer immunity prevalence (SCCAMP) study characterizes the incidence and outcomes of SARS-CoV-2 infection and vaccination in patients with solid tumors undergoing ACT. This preliminary analysis includes 766 patients recruited since May 2020., Methods: Patients with solid-organ cancers attending secondary care for active ACT consented to the collection of routine electronic health record data and serial blood samples over 12 months. Blood samples were tested for total SARS-CoV-2 antibody., Results: A total of 766 participants were recruited between May 28, 2020 and October 31, 2021. Most received cytotoxic chemotherapy (79%). Among the participants, 48 (6.3%) were tested positive for SARS-CoV-2 by PCR. Infection rates were unaffected by ACT, largely aligning with the local population. Mortality proportion was not higher with a recent positive SARS-CoV-2 PCR (10.4% vs 10.6%). Multivariate analysis revealed lower infection rates in vaccinated patients regardless of chemotherapy (HR 0.307 [95% CI, 0.144-0.6548]) or immunotherapy (HR 0.314 [95% CI, 0.041-2.367]) treatment. A total of 96.3% of patients successfully raised SARS-CoV-2 antibodies after >2 vaccines. This was independent of the treatment type., Conclusion: This is the largest on-going longitudinal real-world dataset of patients undergoing ACT during the early stages of the COVID-19 pandemic. This preliminary analysis demonstrates that patients with solid tumors undergoing ACT have high protection from SARS-CoV-2 infection following COVID-19 vaccination. The SCCAMP study will evaluate long-term COVID-19 antibody trends, focusing on specific ACTs and patient subgroups., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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33. The impact of coding germline variants on contralateral breast cancer risk and survival.
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Morra A, Mavaddat N, Muranen TA, Ahearn TU, Allen J, Andrulis IL, Auvinen P, Becher H, Behrens S, Blomqvist C, Bojesen SE, Bolla MK, Brauch H, Camp NJ, Carvalho S, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, Czene K, Decker B, Dennis J, Dörk T, Dorling L, Dunning AM, Ekici AB, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Geurts-Giele WRR, Giles GG, Guénel P, Gündert M, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Heikkilä P, Hooning MJ, Hoppe R, Howell A, Humphreys K, Jakubowska A, Jung AY, Keeman R, Kristensen VN, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Mavroudis D, Milne RL, Mulligan AM, Newman WG, Park-Simon TW, Peterlongo P, Pharoah PDP, Rhenius V, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Spurdle AB, Tomlinson I, Truong T, van Veen EM, Vreeswijk MPG, Wang Q, Wendt C, Yang XR, Nevanlinna H, Devilee P, Easton DF, and Schmidt MK
- Subjects
- Female, Humans, Genes, BRCA2, Germ-Line Mutation, Germ Cells, Genetic Predisposition to Disease, Breast Neoplasms genetics
- Abstract
Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis., Competing Interests: Declaration of interests B.D. is a stockholder of Roche, Vaccitech and EQRx. P.A.F. conducts research funded by Amgen, Novartis, and Pfizer outside the submitted work. He received honoraria from Roche, Novartis, and Pfizer outside the submitted work. D.F.E. is an associate editor at The American Journal of Human Genetics (AJHG)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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34. Prefrontal cortical protease TACE/ADAM17 is involved in neuroinflammation and stress-related eating alterations.
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Sharafeddin F, Ghaly M, Simon TB, Ontiveros-Ángel P, and Figueroa JD
- Abstract
Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme / a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACE/ADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACE/ADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell™ SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACE/ADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACE/ADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations., Competing Interests: DISCLOSURES All authors report no financial interests or potential conflicts of interest.
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- 2023
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35. Impact of tumour characteristics and cancer treatment on cerebrovascular mortality after glioma diagnosis: Evidence from a population-based cancer registry.
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Jin K, Brennan PM, Poon MTC, Figueroa JD, and Sudlow CLM
- Abstract
Objective: We aimed to examine brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment are associated with cerebrovascular mortality among patients with malignant glioma, the most common and aggressive type of brain tumour., Methods: We conducted a retrospective, observational cohort study using the US National Cancer Institute's state and regional population-based cancer registries. We identified adult patients with glioma in 2000 to 2018 (N=72,916). The primary outcome was death from cerebrovascular disease. Cox regression modelling was used to estimate the associations with cerebrovascular mortality of tumour grade, tumour size and treatment (surgery, radiotherapy, chemotherapy), calculating hazard ratios (HR) adjusted for these factors as well as for age, sex, race, marital status and calendar year., Results: Higher grade (Grade IV vs Grade II: HR=2.47, 95% CI=1.69-3.61, p<0.001) and larger brain tumours (size 3 to <6 cm: HR=1.40, 95% CI=1.03 -1.89, p<0.05; size ≥ 6 cm: HR=1.47, 95% CI=1.02-2.13, p<0.05 compared to size < 3cm) were associated with increased cerebrovascular mortality. Cancer treatment was associated with decreased risk (surgery: HR= 0.60, p<0.001; chemotherapy: HR=0.42, p<0.001; radiation: HR= 0.69, p<0.05). However, among patents surviving five years or more from cancer diagnosis radiotherapy was associated with higher risk of cerebrovascular mortality (HR 2.73, 95% CI 1.49-4.99, p<0.01)., Conclusion: More aggressive tumour characteristics are associated with increased cerebrovascular mortality. Radiotherapy increased risk of cerebrovascular mortality five-year after cancer diagnosis. Further research is needed to better understand the long-term cardiovascular consequences of radiation therapy, and whether the consequent risk can be mitigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Brennan, Poon, Figueroa and Sudlow.)
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- 2022
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36. Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.
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Jung AY, Ahearn TU, Behrens S, Middha P, Bolla MK, Wang Q, Arndt V, Aronson KJ, Augustinsson A, Beane Freeman LE, Becher H, Brenner H, Canzian F, Carey LA, Czene K, Eliassen AH, Eriksson M, Evans DG, Figueroa JD, Fritschi L, Gabrielson M, Giles GG, Guénel P, Hadjisavvas A, Haiman CA, Håkansson N, Hall P, Hamann U, Hoppe R, Hopper JL, Howell A, Hunter DJ, Hüsing A, Kaaks R, Kosma VM, Koutros S, Kraft P, Lacey JV, Le Marchand L, Lissowska J, Loizidou MA, Mannermaa A, Maurer T, Murphy RA, Olshan AF, Olsson H, Patel AV, Perou CM, Rennert G, Shibli R, Shu XO, Southey MC, Stone J, Tamimi RM, Teras LR, Troester MA, Truong T, Vachon CM, Wang SS, Wolk A, Wu AH, Yang XR, Zheng W, Dunning AM, Pharoah PDP, Easton DF, Milne RL, Chatterjee N, Schmidt MK, García-Closas M, and Chang-Claude J
- Subjects
- Female, Humans, Receptor, ErbB-2, Receptors, Progesterone, Receptors, Estrogen, Case-Control Studies, Risk Factors, Biomarkers, Tumor, Breast Neoplasms etiology, Breast Neoplasms complications, Triple Negative Breast Neoplasms epidemiology, Triple Negative Breast Neoplasms etiology
- Abstract
Background: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear., Methods: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided., Results: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like., Conclusions: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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37. Implications of differential peroxyl radical-induced inactivation of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase for the pentose phosphate pathway.
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Reyes JS, Fuentes-Lemus E, Figueroa JD, Rojas J, Fierro A, Arenas F, Hägglund PM, Davies MJ, and López-Alarcón C
- Subjects
- Glucosephosphate Dehydrogenase, NADP, Phosphates, Glucose, Phosphogluconate Dehydrogenase, Pentose Phosphate Pathway
- Abstract
Escherichia coli glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) are key enzymes of the pentose phosphate pathway, responsible for the NADPH production in cells. We investigated modification of both enzymes mediated by peroxyl radicals (ROO
· ) to determine their respective susceptibilities to and mechanisms of oxidation. G6PDH and 6PGDH were incubated with AAPH (2,2'-azobis(2-methylpropionamidine)dihydrochloride), which was employed as ROO· source. The enzymatic activities of both enzymes were determined by NADPH release, with oxidative modifications examined by electrophoresis and liquid chromatography (LC) with fluorescence and mass (MS) detection. The activity of G6PDH decreased up to 62.0 ± 15.0% after 180 min incubation with 100 mM AAPH, whilst almost total inactivation of 6PGDH was determined under the same conditions. Although both proteins contain abundant Tyr (particularly 6PGDH), these residues were minimally affected by ROO· , with Trp and Met being major targets. LC-MS and in silico analysis showed that the modification sites of G6PDH are distant to the active site, consistent with a dispersed distribution of modifications, and inactivation resulting from oxidation of multiple Trp and Met residues. In contrast, the sites of oxidation detected on 6PGDH are located close to its catalytic site indicating a more localized oxidation, and a consequent high susceptibility to ROO· -mediated inactivation., (© 2022. The Author(s).)- Published
- 2022
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38. Correction: PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients.
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Giardiello D, Hooning MJ, Hauptmann M, Keeman R, Heemskerk-Gerritsen BAM, Becher H, Blomqvist C, Bojesen SE, Bolla MK, Camp NJ, Czene K, Devilee P, Eccles DM, Fasching PA, Figueroa JD, Flyger H, García-Closas M, Haiman CA, Hamann U, Hopper JL, Jakubowska A, Leeuwen FE, Lindblom A, Lubiński J, Margolin S, Martinez ME, Nevanlinna H, Nevelsteen I, Pelders S, Pharoah PDP, Siesling S, Southey MC, van der Hout AH, van Hest LP, Chang-Claude J, Hall P, Easton DF, Steyerberg EW, and Schmidt MK
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- 2022
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39. Reproductive history differs by molecular subtypes of breast cancer among women aged ≤ 50 years in Scotland diagnosed 2009-2016: a cross-sectional study.
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Chitkara A, Mesa-Eguiagaray I, Wild SH, Hall PS, Cameron DA, Sims AH, and Figueroa JD
- Subjects
- Female, Humans, Pregnancy, Middle Aged, Receptors, Progesterone metabolism, Receptors, Estrogen metabolism, Reproductive History, Cross-Sectional Studies, Receptor, ErbB-2 metabolism, Biomarkers, Tumor metabolism, Breast Neoplasms etiology, Breast Neoplasms genetics, Triple Negative Breast Neoplasms etiology, Triple Negative Breast Neoplasms genetics
- Abstract
Background: The aetiology of breast cancers diagnosed ≤ 50 years of age remains unclear. We aimed to compare reproductive risk factors between molecular subtypes of breast cancer, thereby suggesting possible aetiologic clues, using routinely collected cancer registry and maternity data in Scotland., Methods: We conducted a cross-sectional study of 4108 women aged ≤ 50 years with primary breast cancer diagnosed between 2009 and 2016 linked to maternity data. Molecular subtypes of breast cancer were defined using immunohistochemistry (IHC) tumour markers, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and tumour grade. Age-adjusted polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of number of births, age at first birth and time since last birth with IHC-defined breast cancer subtypes. Luminal A-like was the reference compared to luminal B-like (HER2-), luminal B-like (HER2+), HER2-overexpressed and triple-negative breast cancer (TNBC)., Results: Mean (SD) for number of births, age at first birth and time since last birth was 1.4 (1.2) births, 27.2 (6.1) years and 11.0 (6.8) years, respectively. Luminal A-like was the most common subtype (40%), while HER2-overexpressed and TNBC represented 5% and 15% of cases, respectively. Larger numbers of births were recorded among women with HER2-overexpressed and TNBC compared with luminal A-like tumours (> 3 vs 0 births, OR 1.87, 95%CI 1.18-2.96; OR 1.44, 95%CI 1.07-1.94, respectively). Women with their most recent birth > 10 years compared to < 2 years were less likely to have TNBC tumours compared to luminal A-like (OR 0.63, 95%CI 0.41-0.97). We found limited evidence for differences by subtype with age at first birth., Conclusion: Number of births and time since last birth differed by molecular subtypes of breast cancer among women aged ≤ 50 years. Analyses using linked routine electronic medical records by molecularly defined tumour pathology data can be used to investigate the aetiology and prognosis of cancer., (© 2022. The Author(s).)
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- 2022
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40. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients.
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Giardiello D, Hooning MJ, Hauptmann M, Keeman R, Heemskerk-Gerritsen BAM, Becher H, Blomqvist C, Bojesen SE, Bolla MK, Camp NJ, Czene K, Devilee P, Eccles DM, Fasching PA, Figueroa JD, Flyger H, García-Closas M, Haiman CA, Hamann U, Hopper JL, Jakubowska A, Leeuwen FE, Lindblom A, Lubiński J, Margolin S, Martinez ME, Nevanlinna H, Nevelsteen I, Pelders S, Pharoah PDP, Siesling S, Southey MC, van der Hout AH, van Hest LP, Chang-Claude J, Hall P, Easton DF, Steyerberg EW, and Schmidt MK
- Subjects
- Humans, Female, Mastectomy, Germ-Line Mutation, Risk Factors, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Prophylactic Mastectomy
- Abstract
Background: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors., Methods: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models., Results: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers., Conclusions: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging., (© 2022. The Author(s).)
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- 2022
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41. The oral microbiome and breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in the Ghana Breast Health Study.
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Wu Z, Byrd DA, Wan Y, Ansong D, Clegg-Lamptey JN, Wiafe-Addai B, Edusei L, Adjei E, Titiloye N, Dedey F, Aitpillah F, Oppong J, Vanderpuye V, Osei-Bonsu E, Dagnall CL, Jones K, Hutchinson A, Hicks BD, Ahearn TU, Shi J, Knight R, Biritwum R, Yarney J, Wiafe S, Awuah B, Nyarko K, Figueroa JD, Sinha R, Garcia-Closas M, Brinton LA, and Vogtmann E
- Subjects
- Case-Control Studies, Feces microbiology, Female, Ghana epidemiology, Humans, Logistic Models, Phylogeny, RNA, Ribosomal, 16S genetics, Breast Neoplasms epidemiology, Gastrointestinal Microbiome genetics, Microbiota
- Abstract
The oral microbiome, like the fecal microbiome, may be related to breast cancer risk. Therefore, we investigated whether the oral microbiome was associated with breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in a case-control study in Ghana. A total of 881 women were included (369 breast cancers, 93 nonmalignant cases and 419 population-based controls). The V4 region of the 16S rRNA gene was sequenced from oral and fecal samples. Alpha-diversity (observed amplicon sequence variants [ASVs], Shannon index and Faith's Phylogenetic Diversity) and beta-diversity (Bray-Curtis, Jaccard and weighted and unweighted UniFrac) metrics were computed. MiRKAT and logistic regression models were used to investigate the case-control associations. Oral sample alpha-diversity was inversely associated with breast cancer and nonmalignant breast disease with odds ratios (95% CIs) per every 10 observed ASVs of 0.86 (0.83-0.89) and 0.79 (0.73-0.85), respectively, compared to controls. Beta-diversity was also associated with breast cancer and nonmalignant breast disease compared to controls (P ≤ .001). The relative abundances of Porphyromonas and Fusobacterium were lower for breast cancer cases compared to controls. Alpha-diversity and presence/relative abundance of specific genera from the oral and fecal microbiome were strongly correlated among breast cancer cases, but weakly correlated among controls. Particularly, the relative abundance of oral Porphyromonas was strongly, inversely correlated with fecal Bacteroides among breast cancer cases (r = -.37, P ≤ .001). Many oral microbial metrics were strongly associated with breast cancer and nonmalignant breast disease, and strongly correlated with fecal microbiome among breast cancer cases, but not controls., (© 2022 UICC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
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- 2022
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42. Association of Genetic Ancestry With Terminal Duct Lobular Unit Involution Among Healthy Women.
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Sung H, Koka H, Marino N, Pfeiffer RM, Cora R, Figueroa JD, Sherman ME, Gierach GL, and Yang XR
- Subjects
- Breast, Female, Humans, Incidence, Risk, United States epidemiology, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Mammary Glands, Human, Triple Negative Breast Neoplasms complications, Triple Negative Breast Neoplasms epidemiology, Triple Negative Breast Neoplasms genetics
- Abstract
Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk., (Published by Oxford University Press 2022. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2022
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43. Role of amino acid oxidation and protein unfolding in peroxyl radical and peroxynitrite-induced inactivation of glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides.
- Author
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Figueroa JD, Fuentes-Lemus E, Reyes JS, Loaiza M, Aliaga ME, Fierro A, Leinisch F, Hägglund P, Davies MJ, and López-Alarcón C
- Subjects
- Glucosephosphate Dehydrogenase chemistry, Oxidants chemistry, Oxidation-Reduction, Peroxides, Peroxynitrous Acid, Protein Unfolding, Amino Acids chemistry, Leuconostoc mesenteroides
- Abstract
The mechanisms underlying the inactivation of Leuconostoc mesenteroides glucose 6-phosphate dehydrogenase (G6PDH) induced by peroxyl radicals (ROO
● ) and peroxynitrite (ONOO- ), were explored. G6PDH was incubated with AAPH (2,2' -azobis(2-methylpropionamidine)dihydrochloride), used as ROO● source, and ONOO- . Enzymatic activity was assessed by NADPH generation, while oxidative modifications were analyzed by gel electrophoresis and liquid chromatography (LC) with fluorescence and mass detection. Changes in protein conformation were studied by circular dichroism (CD) and binding of the fluorescent dye ANS (1-anilinonaphthalene-8-sulfonic acid). Incubation of G6PDH (54.4 μM) with 60 mM AAPH showed an initial phase without significant changes in enzymatic activity, followed by a secondary time-dependent continuous decrease in activity to ∼59% of the initial level after 90 min. ONOO- induced a significant and concentration-dependent loss of G6PDH activity with ∼46% of the initial activity lost on treatment with 1.5 mM ONOO- . CD and ANS fluorescence indicated changes in G6PDH secondary structure with exposure of hydrophobic sites on exposure to ROO● , but not ONOO- . LC-MS analysis provided evidence for ONOO- -mediated oxidation of Tyr, Met and Trp residues, with damage to critical Met and Tyr residues underlying enzyme inactivation, but without effects on the native (dimeric) state of the protein. In contrast, studies using chloramine T, a specific oxidant of Met, provided evidence that oxidation of specific Met and Trp residues and concomitant protein unfolding, loss of dimer structure and protein aggregation are involved in G6PDH inactivation by ROO● . These two oxidant systems therefore have markedly different effects on G6PDH structure and activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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44. Incorporating progesterone receptor expression into the PREDICT breast prognostic model.
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Grootes I, Keeman R, Blows FM, Milne RL, Giles GG, Swerdlow AJ, Fasching PA, Abubakar M, Andrulis IL, Anton-Culver H, Beckmann MW, Blomqvist C, Bojesen SE, Bolla MK, Bonanni B, Briceno I, Burwinkel B, Camp NJ, Castelao JE, Choi JY, Clarke CL, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dörk T, Dunning AM, Dwek M, Easton DF, Eccles DM, Eriksson M, Ernst K, Evans DG, Figueroa JD, Fink V, Floris G, Fox S, Gabrielson M, Gago-Dominguez M, García-Sáenz JA, González-Neira A, Haeberle L, Haiman CA, Hall P, Hamann U, Harkness EF, Hartman M, Hein A, Hooning MJ, Hou MF, Howell SJ, Ito H, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kristensen VN, Kwong A, Lambrechts D, Li J, Lubiński J, Manoochehri M, Margolin S, Matsuo K, Taib NAM, Mulligan AM, Nevanlinna H, Newman WG, Offit K, Osorio A, Park SK, Park-Simon TW, Patel AV, Presneau N, Pylkäs K, Rack B, Radice P, Rennert G, Romero A, Saloustros E, Sawyer EJ, Schneeweiss A, Schochter F, Schoemaker MJ, Shen CY, Shibli R, Sinn P, Tapper WJ, Tawfiq E, Teo SH, Teras LR, Torres D, Vachon CM, van Deurzen CHM, Wendt C, Williams JA, Winqvist R, Elwood M, Schmidt MK, García-Closas M, and Pharoah PDP
- Subjects
- Female, Humans, Progesterone, Prognosis, Receptor, ErbB-2 metabolism, Breast Neoplasms pathology, Receptors, Progesterone metabolism
- Abstract
Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2)., Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance., Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10
-6 ) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted., Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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45. Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.
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Doan C, Aouizerat BE, Ye Y, Dang D, Asam K, Bhattacharya A, Howard T, Patel YK, Viet DT, Figueroa JD, Zhong JF, Thomas CM, Morlandt AB, Yu G, Callahan NF, Allen CT, Grandhi A, Herford AS, Walker PC, Nguyen K, Kidd SC, Lee SC, Inman JC, Slater JM, and Viet CT
- Subjects
- Humans, Neoplasm Invasiveness genetics, Neoplasm Recurrence, Local, Neoplastic Processes, Nerve Growth Factors, Nerve Tissue Proteins, Pain, Receptor Protein-Tyrosine Kinases, Receptor, Nerve Growth Factor, Receptor, trkA, Receptors, Nerve Growth Factor genetics, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell genetics, Head and Neck Neoplasms, Mouth Neoplasms genetics
- Abstract
Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain., (© 2022 The Authors. Advanced Biology published by Wiley-VCH GmbH.)
- Published
- 2022
- Full Text
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46. Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations.
- Author
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Ahearn TU, Choudhury PP, Derkach A, Wiafe-Addai B, Awuah B, Yarney J, Edusei L, Titiloye N, Adjei E, Vanderpuye V, Aitpillah F, Dedey F, Oppong J, Osei-Bonsu EB, Duggan MA, Brinton LA, Allen J, Luccarini C, Baynes C, Carvalho S, Dunning AM, Davis Lynn BC, Chanock SJ, Hicks BD, Yeager M, Chatterjee N, Biritwum R, Clegg-Lamptey JN, Nyarko K, Wiafe S, Ansong D, Easton DF, Figueroa JD, and Garcia-Closas M
- Subjects
- Female, Genetic Predisposition to Disease, Ghana epidemiology, Humans, Risk, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Germ-Line Mutation
- Abstract
Background: Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women., Methods: We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women., Results: The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03-46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17-15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15-138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72-6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P < 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks., Conclusions: We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries., Impact: These findings have direct relevance for breast cancer genetic counseling for women in West Africa., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
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47. Fatty Acid-Binding Protein 4 Inhibition Promotes Locomotor and Autonomic Recovery in Rats following Spinal Cord Injury.
- Author
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Licero Campbell J, Serrano-Illàn M, Descorbeth M, Cordero K, Figueroa JD, and De León M
- Subjects
- Animals, Macrophages, Microglia, Rats, Recovery of Function, Spinal Cord metabolism, Biphenyl Compounds therapeutic use, Fatty Acid-Binding Proteins antagonists & inhibitors, Fatty Acid-Binding Proteins metabolism, Locomotion, Pyrazoles therapeutic use, Spinal Cord Injuries
- Abstract
The inflammatory response associated with traumatic spinal cord injury (SCI) contributes to locomotor and sensory impairments. Pro-inflammatory (M1) macrophages/microglia (MϕMG) are the major cellular players in this response as they promote chronic inflammation resulting in injury expansion and tissue damage. Fatty acid-binding protein 4 (FABP4) promotes M1 MϕMG differentiation; however, it is unknown if FABP4 also plays a role in the etiology of SCI. The present study investigates whether FABP4's gene expression influences functional recovery following SCI. Analysis of quantitative polymerase chain reaction data shows a robust induction of FABP4 messenger RNA (mRNA; >100 fold) in rats subjected to a T9-T10 contusion injury compared with control. Western blot experiments reveal significant upregulation of FABP4 protein at the injury epicenter, and immunofluorescence analysis identifies that this upregulation occurs in CD11b
+ MϕMG. Further, upregulation of FABP4 gene expression correlates with peroxisome proliferator-activated receptor γ (PPARγ) downregulation, inactivation of Iκβα, and the activation of the NF-κB pathway. Analysis of locomotor recovery using the Basso-Beattie-Bresnahan's locomotor scale and the CatWalk gait analysis system shows that injured rats treated with FABP4 inhibitor BMS309403 have significant improvements in locomotion compared with vehicle controls. Additionally, inhibitor-treated rats exhibit enhanced autonomic bladder reflex recovery. Immunofluorescence experiments also show the administration of the FABP4 inhibitor increases the number of CD163+ and liver arginase+ M2 MϕMG within the epicenter and penumbra of the injured spinal cord 28 days post-injury. These findings show that FABP4 may significantly exacerbate locomotor and sensory impairments during SCI by modulating macrophage/microglial activity.- Published
- 2022
- Full Text
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48. Breast cancer incidence and survival in Scotland by socio-economic deprivation and tumour subtype.
- Author
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Mesa-Eguiagaray I, Wild SH, Bird SM, Williams LJ, Brewster DH, Hall PS, and Figueroa JD
- Subjects
- Educational Status, Female, Humans, Incidence, Income, Poverty, Socioeconomic Factors, Breast Neoplasms
- Abstract
Background: Women from socio-economically deprived areas are less likely to develop and then to survive breast cancer (BC). Whether associations between deprivation and BC incidence and survival differ by tumour molecular subtypes and mode of detection in Scotland are unknown., Methods: Data consisted of 62,378 women diagnosed with invasive BC between 2000 and 2016 in Scotland. Incidence rates and time trends were calculated for oestrogen receptor positive (ER+) and negative (ER-) tumours and stratified by the Scottish Index of Multiple Deprivation (SIMD) quintiles and screening status. SIMD is an area-based measure derived across seven domains: income, employment, education, health, access to services, crime and housing. We calculated adjusted hazard ratios (aHR [95% confidence intervals]) for BC death by immunohistochemical surrogates of molecular subtypes for the most versus the least deprived quintile. We adjusted for mode of detection and other confounders., Results: In Scotland, screen-detected ER+tumour incidence increased over time, particularly in the least deprived quintile [Average Annual Percentage Change (AAPC) = 2.9% with 95% CI from 1.2 to 4.7]. No marked differences were observed for non-screen-detected ER+tumours or ER- tumours by deprivation. BC mortality was higher in the most compared to the least deprived quintile irrespective of ER status (aHR = 1.29 [1.18, 1.41] for ER+ and 1.27 [1.09, 1.47] for ER- tumours). However, deprivation was associated with significantly higher mortality for luminal A and HER2-enriched tumours (aHR = 1.46 [1.13, 1.88] and 2.10 [1.23, 3.59] respectively) but weaker associations for luminal B and TNBC tumours that were not statistically significant., Conclusions: Deprivation is associated with differential BC incidence trends for screen-detected ER+tumours and with higher mortality for select tumour subtypes. Future efforts should evaluate factors that might be associated with reduced survival in deprived populations and monitor progress stratified by tumour subtypes and mode of detection., (© 2022. The Author(s).)
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- 2022
- Full Text
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49. Standardizing reporting of brain and central nervous system tumors in the United Kingdom.
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Poon MTC, Brennan PM, Jin K, Sudlow CLM, and Figueroa JD
- Subjects
- Brain pathology, Humans, United Kingdom epidemiology, Brain Neoplasms epidemiology, Central Nervous System Neoplasms epidemiology, Central Nervous System Neoplasms pathology
- Published
- 2022
- Full Text
- View/download PDF
50. Hypothesis: Amelioration of obesity-induced cognitive dysfunction via a lorcaserin-betahistine combination treatment.
- Author
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Dela Peña IC, Figueroa JD, and Shi WX
- Subjects
- Animals, Benzazepines, Dopamine, Obesity complications, Obesity drug therapy, Rats, Rats, Sprague-Dawley, Betahistine pharmacology, Betahistine therapeutic use, Cognitive Dysfunction drug therapy, Cognitive Dysfunction etiology
- Abstract
The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity-associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity-linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5-HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity-induced cognitive dysfunction. We propose to test the hypothesis in a diet-induced obesity (DIO) rat model by treating animals with the 5-HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes., (© 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2022
- Full Text
- View/download PDF
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