68 results on '"Gokgoz, N"'
Search Results
2. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I)
- Author
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Onay, T., Topaloglu, O., Zielenski, J., Gokgoz, N., Kayserili, H., Camcioglu, Y., Cokugras, H., Akcakaya, N., Apak, M., Tsui, L.-C., and Kirdar, B.
- Published
- 1998
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3. Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients
- Author
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Koster, R. (Roelof), Panagiotou, O.A. (Orestis A.), Wheeler, W. (William), Karlins, E. (Eric), Gastier-Foster, J.M. (Julie M.), Caminada-de-Toledo, S.R. (Silvia Regina), Petrilli, A.S. (Antonio S.), Flanagan, A.M. (Adrienne M.), Tirabosco, R. (Roberto), Andrulis, I.L. (Irene L.), Wunder, J.S. (Jay S.), Gokgoz, N. (Nalan), Patiño-García, A. (Ana), Lecanda, F. (Fernando), Serra, M. (Massimo), Hattinger, C. (Claudia), Picci, P. (Piero), Scotlandi, K. (Katia), Thomas, D.M. (David M.), Ballinger, M.L. (Mandy L.), Gorlick, R.G. (Richard G.), Barkauskas, D.A. (Donald A.), Spector, L. (Logan), Tucker, M. (Margaret), Hicks, B. (Belynda), Yeager, M. (Meredith), Hoover, R.N. (Robert N.), Wacholder, S. (Sholom), Chanock, S.J. (Stephen J.), Savage, S.A. (Sharon A.), and Mirabello, L. (Lisa)
- Subjects
Osteosarcoma ,Genome-wide association study ,Overall survival ,Osteosarcoma-specific survival - Abstract
Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease.
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- 2018
4. Analysis of gene expression patterns in breast cancer by microarray technology
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Gokgoz, N., Woodget, J., Sun, X., Bull, S., and Andrulis, I.L.
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Genetic research -- Analysis ,Human genetics -- Research ,Breast cancer -- Genetic aspects ,Gene expression -- Research ,Biological sciences - Published
- 2000
5. 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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Wang, Z., primary, Zhu, B., additional, Zhang, M., additional, Parikh, H., additional, Jia, J., additional, Chung, C. C., additional, Sampson, J. N., additional, Hoskins, J. W., additional, Hutchinson, A., additional, Burdette, L., additional, Ibrahim, A., additional, Hautman, C., additional, Raj, P. S., additional, Abnet, C. C., additional, Adjei, A. A., additional, Ahlbom, A., additional, Albanes, D., additional, Allen, N. E., additional, Ambrosone, C. B., additional, Aldrich, M., additional, Amiano, P., additional, Amos, C., additional, Andersson, U., additional, Andriole, G., additional, Andrulis, I. L., additional, Arici, C., additional, Arslan, A. A., additional, Austin, M. A., additional, Baris, D., additional, Barkauskas, D. A., additional, Bassig, B. A., additional, Beane Freeman, L. E., additional, Berg, C. D., additional, Berndt, S. I., additional, Bertazzi, P. A., additional, Biritwum, R. B., additional, Black, A., additional, Blot, W., additional, Boeing, H., additional, Boffetta, P., additional, Bolton, K., additional, Boutron-Ruault, M.-C., additional, Bracci, P. M., additional, Brennan, P., additional, Brinton, L. A., additional, Brotzman, M., additional, Bueno-de-Mesquita, H. B., additional, Buring, J. E., additional, Butler, M. A., additional, Cai, Q., additional, Cancel-Tassin, G., additional, Canzian, F., additional, Cao, G., additional, Caporaso, N. E., additional, Carrato, A., additional, Carreon, T., additional, Carta, A., additional, Chang, G.-C., additional, Chang, I.-S., additional, Chang-Claude, J., additional, Che, X., additional, Chen, C.-J., additional, Chen, C.-Y., additional, Chen, C.-H., additional, Chen, C., additional, Chen, K.-Y., additional, Chen, Y.-M., additional, Chokkalingam, A. P., additional, Chu, L. W., additional, Clavel-Chapelon, F., additional, Colditz, G. A., additional, Colt, J. S., additional, Conti, D., additional, Cook, M. B., additional, Cortessis, V. K., additional, Crawford, E. D., additional, Cussenot, O., additional, Davis, F. G., additional, De Vivo, I., additional, Deng, X., additional, Ding, T., additional, Dinney, C. P., additional, Di Stefano, A. L., additional, Diver, W. R., additional, Duell, E. J., additional, Elena, J. W., additional, Fan, J.-H., additional, Feigelson, H. S., additional, Feychting, M., additional, Figueroa, J. D., additional, Flanagan, A. M., additional, Fraumeni, J. F., additional, Freedman, N. D., additional, Fridley, B. L., additional, Fuchs, C. S., additional, Gago-Dominguez, M., additional, Gallinger, S., additional, Gao, Y.-T., additional, Gapstur, S. M., additional, Garcia-Closas, M., additional, Garcia-Closas, R., additional, Gastier-Foster, J. M., additional, Gaziano, J. M., additional, Gerhard, D. S., additional, Giffen, C. A., additional, Giles, G. G., additional, Gillanders, E. M., additional, Giovannucci, E. L., additional, Goggins, M., additional, Gokgoz, N., additional, Goldstein, A. M., additional, Gonzalez, C., additional, Gorlick, R., additional, Greene, M. H., additional, Gross, M., additional, Grossman, H. B., additional, Grubb, R., additional, Gu, J., additional, Guan, P., additional, Haiman, C. A., additional, Hallmans, G., additional, Hankinson, S. E., additional, Harris, C. C., additional, Hartge, P., additional, Hattinger, C., additional, Hayes, R. B., additional, He, Q., additional, Helman, L., additional, Henderson, B. E., additional, Henriksson, R., additional, Hoffman-Bolton, J., additional, Hohensee, C., additional, Holly, E. A., additional, Hong, Y.-C., additional, Hoover, R. N., additional, Hosgood, H. D., additional, Hsiao, C.-F., additional, Hsing, A. W., additional, Hsiung, C. A., additional, Hu, N., additional, Hu, W., additional, Hu, Z., additional, Huang, M.-S., additional, Hunter, D. J., additional, Inskip, P. D., additional, Ito, H., additional, Jacobs, E. J., additional, Jacobs, K. B., additional, Jenab, M., additional, Ji, B.-T., additional, Johansen, C., additional, Johansson, M., additional, Johnson, A., additional, Kaaks, R., additional, Kamat, A. M., additional, Kamineni, A., additional, Karagas, M., additional, Khanna, C., additional, Khaw, K.-T., additional, Kim, C., additional, Kim, I.-S., additional, Kim, J. H., additional, Kim, Y. H., additional, Kim, Y.-C., additional, Kim, Y. T., additional, Kang, C. H., additional, Jung, Y. J., additional, Kitahara, C. M., additional, Klein, A. P., additional, Klein, R., additional, Kogevinas, M., additional, Koh, W.-P., additional, Kohno, T., additional, Kolonel, L. N., additional, Kooperberg, C., additional, Kratz, C. P., additional, Krogh, V., additional, Kunitoh, H., additional, Kurtz, R. C., additional, Kurucu, N., additional, Lan, Q., additional, Lathrop, M., additional, Lau, C. C., additional, Lecanda, F., additional, Lee, K.-M., additional, Lee, M. P., additional, Le Marchand, L., additional, Lerner, S. P., additional, Li, D., additional, Liao, L. M., additional, Lim, W.-Y., additional, Lin, D., additional, Lin, J., additional, Lindstrom, S., additional, Linet, M. S., additional, Lissowska, J., additional, Liu, J., additional, Ljungberg, B., additional, Lloreta, J., additional, Lu, D., additional, Ma, J., additional, Malats, N., additional, Mannisto, S., additional, Marina, N., additional, Mastrangelo, G., additional, Matsuo, K., additional, McGlynn, K. A., additional, McKean-Cowdin, R., additional, McNeill, L. H., additional, McWilliams, R. R., additional, Melin, B. S., additional, Meltzer, P. S., additional, Mensah, J. E., additional, Miao, X., additional, Michaud, D. S., additional, Mondul, A. M., additional, Moore, L. E., additional, Muir, K., additional, Niwa, S., additional, Olson, S. H., additional, Orr, N., additional, Panico, S., additional, Park, J. Y., additional, Patel, A. V., additional, Patino-Garcia, A., additional, Pavanello, S., additional, Peeters, P. H. M., additional, Peplonska, B., additional, Peters, U., additional, Petersen, G. M., additional, Picci, P., additional, Pike, M. C., additional, Porru, S., additional, Prescott, J., additional, Pu, X., additional, Purdue, M. P., additional, Qiao, Y.-L., additional, Rajaraman, P., additional, Riboli, E., additional, Risch, H. A., additional, Rodabough, R. J., additional, Rothman, N., additional, Ruder, A. M., additional, Ryu, J.-S., additional, Sanson, M., additional, Schned, A., additional, Schumacher, F. R., additional, Schwartz, A. G., additional, Schwartz, K. L., additional, Schwenn, M., additional, Scotlandi, K., additional, Seow, A., additional, Serra, C., additional, Serra, M., additional, Sesso, H. D., additional, Severi, G., additional, Shen, H., additional, Shen, M., additional, Shete, S., additional, Shiraishi, K., additional, Shu, X.-O., additional, Siddiq, A., additional, Sierrasesumaga, L., additional, Sierri, S., additional, Loon Sihoe, A. D., additional, Silverman, D. T., additional, Simon, M., additional, Southey, M. C., additional, Spector, L., additional, Spitz, M., additional, Stampfer, M., additional, Stattin, P., additional, Stern, M. C., additional, Stevens, V. L., additional, Stolzenberg-Solomon, R. Z., additional, Stram, D. O., additional, Strom, S. S., additional, Su, W.-C., additional, Sund, M., additional, Sung, S. W., additional, Swerdlow, A., additional, Tan, W., additional, Tanaka, H., additional, Tang, W., additional, Tang, Z.-Z., additional, Tardon, A., additional, Tay, E., additional, Taylor, P. R., additional, Tettey, Y., additional, Thomas, D. M., additional, Tirabosco, R., additional, Tjonneland, A., additional, Tobias, G. S., additional, Toro, J. R., additional, Travis, R. C., additional, Trichopoulos, D., additional, Troisi, R., additional, Truelove, A., additional, Tsai, Y.-H., additional, Tucker, M. A., additional, Tumino, R., additional, Van Den Berg, D., additional, Van Den Eeden, S. K., additional, Vermeulen, R., additional, Vineis, P., additional, Visvanathan, K., additional, Vogel, U., additional, Wang, C., additional, Wang, J., additional, Wang, S. S., additional, Weiderpass, E., additional, Weinstein, S. J., additional, Wentzensen, N., additional, Wheeler, W., additional, White, E., additional, Wiencke, J. K., additional, Wolk, A., additional, Wolpin, B. M., additional, Wong, M. P., additional, Wrensch, M., additional, Wu, C., additional, Wu, T., additional, Wu, X., additional, Wu, Y.-L., additional, Wunder, J. S., additional, Xiang, Y.-B., additional, Xu, J., additional, Yang, H. P., additional, Yang, P.-C., additional, Yatabe, Y., additional, Ye, Y., additional, Yeboah, E. D., additional, Yin, Z., additional, Ying, C., additional, Yu, C.-J., additional, Yu, K., additional, Yuan, J.-M., additional, Zanetti, K. A., additional, Zeleniuch-Jacquotte, A., additional, Zheng, W., additional, Zhou, B., additional, Mirabello, L., additional, Savage, S. A., additional, Kraft, P., additional, Chanock, S. J., additional, Yeager, M., additional, Landi, M. T., additional, Shi, J., additional, Chatterjee, N., additional, and Amundadottir, L. T., additional
- Published
- 2014
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6. Genome-wide association study identifies two susceptibility loci for osteosarcoma
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Savage, SA, Mirabello, L, Wang, Z, Gastier-Foster, JM, Gorlick, R, Khanna, C, Flanagan, AM, Tirabosco, R, Andrulis, IL, Wunder, JS, Gokgoz, N, Patino-Garcia, A, Sierrasesumaga, L, Lecanda, F, Kurucu, N, Ilhan, IE, Sari, N, Serra, M, Hattinger, C, Picci, P, Spector, LG, Barkauskas, DA, Marina, N, Caminada de Toledo, SR, Petrilli, AS, Amary, MF, Halai, D, Thomas, DM, Douglass, C, Meltzer, PS, Jacobs, K, Chung, CC, Berndt, SI, Purdue, MP, Caporaso, NE, Tucker, M, Rothman, N, Landi, MT, Silverman, DT, Kraft, P, Hunter, DJ, Malats, N, Kogevinas, M, Wacholder, S, Troisi, R, Helman, L, Fraumeni, JF, Yeager, M, Hoover, RN, Chanock, SJ, Savage, SA, Mirabello, L, Wang, Z, Gastier-Foster, JM, Gorlick, R, Khanna, C, Flanagan, AM, Tirabosco, R, Andrulis, IL, Wunder, JS, Gokgoz, N, Patino-Garcia, A, Sierrasesumaga, L, Lecanda, F, Kurucu, N, Ilhan, IE, Sari, N, Serra, M, Hattinger, C, Picci, P, Spector, LG, Barkauskas, DA, Marina, N, Caminada de Toledo, SR, Petrilli, AS, Amary, MF, Halai, D, Thomas, DM, Douglass, C, Meltzer, PS, Jacobs, K, Chung, CC, Berndt, SI, Purdue, MP, Caporaso, NE, Tucker, M, Rothman, N, Landi, MT, Silverman, DT, Kraft, P, Hunter, DJ, Malats, N, Kogevinas, M, Wacholder, S, Troisi, R, Helman, L, Fraumeni, JF, Yeager, M, Hoover, RN, and Chanock, SJ
- Abstract
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
- Published
- 2013
7. Abstract 4917: PRKCE and other genetic networks in osteosarcoma metastasis
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Goudarzi, Atta, primary, Gokgoz, N., additional, Gill, M., additional, Wunder, J. S., additional, and Andrulis, I. L., additional
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- 2011
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8. p53 missense but not truncation mutations are associated with low levels of p21CIP1/WAF1mRNA expression in primary human sarcomas
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Mousses, S, primary, Gokgoz, N, additional, Wunder, J S, additional, Ozcelik, H, additional, Bull, S, additional, Bell, R S, additional, and Andrulis, I L, additional
- Published
- 2001
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9. 720 A Novel Genetic Syndrome of Posterior Fossa Tumors of Infancy Secondary to Germline Mutation of hSNF5
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Taylor, Michael D., primary, Gokgoz, N., additional, Andrulis, I., additional, Mainprize, T. G., additional, Jun, P., additional, Drake, James, additional, and Rutka, James T., additional
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- 2000
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10. Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma.
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Gokgoz, Nalan, Wunder, Jay S., Mousses, Spyro, Eskandarian, Sasha, Bell, Robert S., Andrulis, Irene L., Gokgoz, N, Wunder, J S, Mousses, S, Eskandarian, S, Bell, R S, and Andrulis, I L
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- 2001
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11. p53 missense but not truncation mutations are associated with low levels of p21CIP1/WAF1mRNA expression in primary human sarcomas.
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Mousses, S, Gokgoz, N, Wunder, J S, Ozcelik, H, Bull, S, Bell, R S, and Andrulis, I L
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SARCOMA , *GENETIC mutation - Abstract
Many growth-suppressing signals converge to control the levels of the CDK inhibitor p21[SUPCIP1/WAF1]. Some human cancers exhibit low levels of expression of p21[SUPCIP1/WAF1]and mutations inp53 have been implicated in this down-regulation. To evaluate whether the presence of p53 mutations was related to the in vivo expression of p21[SUPCIP1/WAF1] mRNA in sarcomas we measured the p21[SUPCIP1/WAF1] mRNA levels for a group of 71 primary bone and soft tissue tumours with known p53 status. As expected, most tumours withp53 mutations expressed low levels of p21[SUPCIP1/WAF1] mRNA. However, we identified a group of tumours withp53 gene mutations that exhibited normal or higher levels ofp21[SUPCIP1/WAF1] mRNA. The p53 mutations in the latter group were not the common missense mutations in exons 4-9, but were predominantly nonsense mutations predicted to result in truncation of the p53 protein. The results of this study suggest that different types ofp53 mutations can have different effects on the expression of downstream genes such as p21[SUPCIP1/WAF1] in human sarcomas. [ABSTRACT FROM AUTHOR]
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- 2001
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12. Expression of Osteocalcin and its Transcriptional Regulators Core-Binding Factor Alpha 1 and MSX2 in Osteoid-forming Tumours
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Hopyan, S., Gokgoz, N., Bell, R. S., Andrulis, I. L., Alman, B. A., and Wunder, J. S.
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- 1999
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13. Cystic Fibrosis Mutation and Associated Haplotypes in Turkish Cystic Fibrosis Patients
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Onay, Tuncer, Zielenski, Julian, Topaloglu, Ozlem, Gokgoz, Nalan, Kayserili, Hulya, Apak, Memnune Yuksel, Camcioglu, Yildiz, Cokugras, Haluk, Akcakaya, Necla, Tsui, Lap-Chee, and Kirdar, Betul
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- 2001
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14. Deletion analysis of SMNtel, NAIP and BTF2p44tel genes in Turkish SMA families
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Savas, S., Gokgoz, N., Hülya Kayserili, Ozkinay, F., Apak, M., Kirdar, B., and Ege Üniversitesi
- Abstract
WOS: 000074522800622
15. 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
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16. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
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Stolzenberg-Solomon, Bengt Glimelius, Wei Hu, Maria Dolores Chirlaque, Kimberly A. Bertrand, Bruce K. Armstrong, Veronica Wendy Setiawan, Kathy J. Helzlsouer, Manal M. Hassan, Jun Yokota, David V. Conti, Kai Yu, Chenwei Liu, Christine F. Skibola, Jae Yong Park, Fernando Lecanda, Dimitrios Trichopoulos, Eleanor Kane, Dongxin Lin, Yun-Chul Hong, Consol Serra, Anne Tjønneland, Melissa A. Austin, X. Zhang, Charles S. Fuchs, Nathaniel Rothman, Paul Brennan, Chih-Liang Wang, Wei Shen, Ying-Huang Tsai, Hee Nam Kim, Ghislaine Scelo, Faith G. Davis, Sara Lindström, Molly Schwenn, Giuseppe Mastrangelo, Adeline Seow, Laufey T. Amundadottir, Laura E. Beane Freeman, Huan Guo, Victor Ho-Fun Lee, Aruna Kamineni, Pierluigi Cocco, Jiang Chang, Emanuele Angelucci, Paige M. Bracci, Yong-Bing Xiang, G. M. Monawar Hosain, Elisabete Weiderpass, James R. Cerhan, Junjie Wu, Lauren R. Teras, Jin Hee Kim, Qiuyin Cai, Sampson, J.N., Wheeler, W.A., Yeager, M., Panagiotou, O., Wang, Z., Berndt, S.I., Lan, Q., Abnet, C.C., Amundadottir, L.T., Figueroa, J.D., Landi, M.T., Mirabello, L., Savage, S.A., Taylor, P.R., De Vivo, I., McGlynn, K.A., Purdue, M.P., Rajaraman, P., Adami, H.-O., Ahlbom, A., Albanes, D., Amary, M.F., An, S.-J., Andersson, U., Andriole, G., Jr., Andrulis, I.L., Angelucci, E., Ansell, S.M., Arici, C., Armstrong, B.K., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Becker, N., Benavente, Y., Benhamou, S., Berg, C., Van Den Berg, D., Bernstein, L., Bertrand, K.A., Birmann, B.M., Black, A., Boeing, H., Boffetta, P., Boutron-Ruault, M.-C., Bracci, P.M., Brinton, L., Brooks-Wilson, A.R., Bueno-De-Mesquita, H.B., Burdett, L., Buring, J., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Carrato, A., Carreon, T., Carta, A., Chan, J.K.C., Chang, E.T., Chang, G.-C., Chang, I.S., Chang, J., Chang-Claude, J., Chen, C.-J., Chen, C.-Y., Chen, C., Chen, C.-H., Chen, H., Chen, K., Chen, K.-Y., Chen, K.-C., Chen, Y., Chen, Y.-H., Chen, Y.-S., Chen, Y.-M., Chien, L.-H., Chirlaque, M.-D., Choi, J.E., Choi, Y.Y., Chow, W.-H., Chung, C.C., Clavel, J., Clavel-Chapelon, F., Cocco, P., Colt, J.S., Comperat, E., Conde, L., Connors, J.M., Conti, D., Cortessis, V.K., Cotterchio, M., Cozen, W., Crouch, S., Crous-Bou, M., Cussenot, O., Davis, F.G., Ding, T., Diver, W.R., Dorronsoro, M., Dossus, L., Duell, E.J., Ennas, M.G., Erickson, R.L., Feychting, M., Flanagan, A.M., Foretova, L., Fraumeni, J.F., Jr., Freedman, N.D., Freeman, L.E.B., Fuchs, C., Gago-Dominguez, M., Gallinger, S., Gao, Y.-T., Gapstur, S.M., Garcia-Closas, M., García-Closas, R., Gascoyne, R.D., Gastier-Foster, J., Gaudet, M.M., Gaziano, J.M., Giffen, C., Giles, G.G., Giovannucci, E., Glimelius, B., Goggins, M., Gokgoz, N., Goldstein, A.M., Gorlick, R., Gross, M., Grubb, R., III and Gu, J., Guan, P., Gunter, M., Guo, H., Habermann, T.M., Haiman, C.A., Halai, D., Hallmans, G., Hassan, M., Hattinger, C., He, Q., He, X., Helzlsouer, K., Henderson, B., Henriksson, R., Hjalgrim, H., Hoffman-Bolton, J., Hohensee, C., Holford, T.R., Holly, E.A., Hong, Y.-C., Hoover, R.N., Horn-Ross, P.L., Hosain, G.M.M., Hosgood, H.D., III and Hsiao, C.-F., Hu, N., Hu, W., Hu, Z., Huang, M.-S., Huerta, J.-M., Hung, J.-Y., Hutchinson, A., Inskip, P.D., Jackson, R.D., Jacobs, E.J., Jenab, M., Jeon, H.-S., Ji, B.-T., Jin, G., Jin, L., Johansen, C., Johnson, A., Jung, Y.J., Kaaks, R., Kamineni, A., Kane, E., Kang, C.H., Karagas, M.R., Kelly, R.S., Khaw, K.-T., Kim, C., Kim, H.N., Kim, J.H., Kim, J.S., Kim, Y.H., Kim, Y.T., Kim, Y.-C., Kitahara, C.M., Klein, A.P., Klein, R.J., Kogevinas, M., Kohno, T., Kolonel, L.N., Kooperberg, C., Kricker, A., Krogh, V., Kunitoh, H., Kurtz, R.C., Kweon, S.-S., La Croix, A., Lawrence, C., Lecanda, F., Lee, V.H.F., Li, D., Li, H., Li, J., Li, Y.-J., Li, Y., Liao, L.M., Liebow, M., Lightfoot, T., Lim, W.-Y., Lin, C.-C., Lin, D., Lindstrom, S., Linet, M.S., Link, B.K., Liu, C., Liu, J., Liu, L., Ljungberg, B., Lloreta, J., Di Lollo, S., Lu, D., Lund, E., Malats, N., Mannisto, S., Marchand, L.L., Marina, N., Masala, G., Mastrangelo, G., Matsuo, K., Maynadie, M., McKay, J., McKean-Cowdin, R., Melbye, M., Melin, B.S., Michaud, D.S., Mitsudomi, T., Monnereau, A., Montalvan, R., Moore, L.E., Mortensen, L.M., Nieters, A., North, K.E., Novak, A.J., Oberg, A.L., Offit, K., Oh, I.-J., Olson, S.H., Palli, D., Pao, W., Park, I.K., Park, J.Y., Park, K.H., Patiño-Garcia, A., Pavanello, S., Peeters, P.H.M., Perng, R.-P., Peters, U., Petersen, G.M., Picci, P., Pike, M.C., Porru, S., Prescott, J., Prokunina-Olsson, L., Qian, B., Qiao, Y.-L., Rais, M., Riboli, E., Riby, J., Risch, H.A., Rizzato, C., Rodabough, R., Roman, E., Roupret, M., Ruder, A.M., De Sanjose, S., Scelo, G., Schned, A., Schumacher, F., Schwartz, K., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H.D., Setiawan, V.W., Severi, G., Severson, R.K., Shanafelt, T.D., Shen, H., Shen, W., Shin, M.-H., Shiraishi, K., Shu, X.-O., Siddiq, A., Sierrasesúmaga, L., Sihoe, A.D.L., Skibola, C.F., Smith, A., Smith, M.T., Southey, M.C., Spinelli, J.J., Staines, A., Stampfer, M., Stern, M.C., Stevens, V.L., Stolzenberg-Solomon, R.S., Su, J., Su, W.-C., Sund, M., Sung, J.S., Sung, S.W., Tan, W., Tang, W., Tardón, A., Thomas, D., Thompson, C.A., Tinker, L.F., Tirabosco, R., Tjønneland, A., Travis, R.C., Trichopoulos, D., Tsai, F.-Y., Tsai, Y.-H., Tucker, M., Turner, J., Vajdic, C.M., Vermeulen, R.C.H., Villano, D.J., Vineis, P., Virtamo, J., Visvanathan, K., Wactawski-Wende, J., Wang, C., Wang, C.-L., Wang, J.-C., Wang, J., Wei, F., Weiderpass, E., Weiner, G.J., Weinstein, S., Wentzensen, N., White, E., Witzig, T.E., Wolpin, B.M., Wong, M.P., Wu, C., Wu, G., Wu, J., Wu, T., Wu, W., Wu, X., Wu, Y.-L., Wunder, J.S., Xiang, Y.-B., Xu, J., Xu, P., Yang, P.-C., Yang, T.-Y., Ye, Y., Yin, Z., Yokota, J., Yoon, H.-I., Yu, C.-J., Yu, H., Yu, K., Yuan, J.-M., Zelenetz, A., Zeleniuch-Jacquotte, A., Zhang, X.-C., Zhang, Y., Zhao, X., Zhao, Z., Zheng, H., Zheng, T., Zheng, W., Zhou, B., Zhu, M., Zucca, M., Boca, S.M., Cerhan, J.R., Ferri, G.M., Hartge, P., Hsiung, C.A., Magnani, C., Miligi, L., Morton, L.M., Smedby, K.E., Teras, L.R., Vijai, J., Wang, S.S., Brennan, P., Caporaso, N.E., Hunter, D.J., Kraft, P., Rothman, N., Silverman, D.T., Slager, S.L., Chanock, S.J., Chatterjee, N., Infection & Immunity, dIRAS RA-I&I RA, LS IRAS EEPI GRA (Gezh.risico-analyse), and Risk Assessment
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Male ,Cancer Research ,Lung Neoplasms ,Lymphoma ,Genome-wide association study ,Polymorphism (computer science) ,Neoplasms ,Medicine ,Chronic ,Genetics ,Osteosarcoma ,Oncology And Carcinogenesis ,Leukemia ,Smoking ,Family aggregation ,Single Nucleotide ,Middle Aged ,Familial risk ,Diffuse ,Kidney Neoplasms ,Lymphocytic ,Oncology ,Adult ,Aged ,Asian Continental Ancestry Group ,Bone Neoplasms ,European Continental Ancestry Group ,Female ,Humans ,Leukemia, Lymphocytic, Chronic, B-Cell ,Lymphoma, Large B-Cell, Diffuse ,Polymorphism, Single Nucleotide ,Testicular Neoplasms ,Tissue Array Analysis ,Urinary Bladder Neoplasms ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genetic correlation ,Large B-Cell ,Oncology & Carcinogenesis ,Polymorphism ,business.industry ,Extramural ,B-Cell ,Cancer ,Heritability ,Genome-wide association studies for thirteen cancer types ,medicine.disease ,business - Abstract
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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- 2015
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17. Identification of Malignancy in Peritumoral Edema in Soft Tissue Sarcoma: A Novel Targeted Molecular Approach.
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Principe MAV, Gokgoz N, Prochazka P, Coward VS, Saini S, MacParland S, Gladdy R, Ferguson P, Wunder JS, Andrulis IL, Chung P, Griffin AM, White LM, Dickson BC, and Tsoi KM
- Abstract
Background: Peritumoral edema on staging magnetic resonance imaging (MRI) is associated with higher local recurrence in soft tissue sarcoma (STS). This may relate to the presence of satellite malignant cells that are difficult to distinguish from benign atypia, leading to over- or undertreatment. This study evaluated a novel targeted molecular approach to identify malignancy in STS peritumoral planes as a means to improve personalized care., Methods: In the targeted molecular approach, whole-exome sequencing was employed to identify tumor-specific variants (TSVs), and peritumoral planes were assayed for malignancy, defined as two or more TSVs/plane, using droplet digital polymerase chain reaction (PCR). Feasibility was evaluated using a retrospective cohort (n = 8) in which planes with cellular atypia were tested. A prospective cohort (n = 8) then assayed all peritumoral planes with radiologic edema., Results: The targeted molecular approach identified malignancy in three of eight cases with cellular atypia of unknown significance (37.5%) and five of eight cases with peritumoral edema on staging MRI (62.5%). Peritumoral regions were heterogeneous; in none of the malignant cases did all sampled planes have evidence of tumor. Malignancy was also identified in regions without cellular atypia. Both cases with a local recurrence had molecular evidence of malignancy outside the main mass despite R0 margins., Conclusion: This study describes a novel personalized approach to detect malignancy in peritumoral regions in STS and is the first to identify molecular evidence of tumor outside the main mass. While development of a clinical tool is underway, these findings support the current approach of treating all peritumoral edema as malignant., Competing Interests: Disclosure Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Victoria S. Coward, Sidharth Saini, Sonya MacParland, Rebecca Gladdy, Peter Ferguson, Jay S. Wunder, Irene L. Andrulis, Peter Chung, Anthony M. Griffin, Lawrence M. White, Brendan C. Dickson, and Kim M. Tsoi have no potential conflicts of interest to declare that may be relevant to the contents of this study., (© 2024. Society of Surgical Oncology.)
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- 2024
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18. Epigenomic and Transcriptomic Profiling of Solitary Fibrous Tumors Identifies Site-Specific Patterns and Candidate Genes Regulated by DNA Methylation.
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Beird HC, Cloutier JM, Gokgoz N, Eeles C, Griffin AM, Ingram DR, Wani KM, Segura RL, Cohen L, Ho C, Wunder JS, Andrulis IL, Futreal PA, Haibe-Kains B, Lazar AJ, Wang WL, Przybyl J, and Demicco EG
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- Humans, Middle Aged, Female, Male, Aged, Adult, Epigenomics methods, Gene Expression Regulation, Neoplastic, Epigenesis, Genetic, Transcriptome, Aged, 80 and over, Solitary Fibrous Tumors genetics, Solitary Fibrous Tumors pathology, Solitary Fibrous Tumors metabolism, DNA Methylation, Gene Expression Profiling
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A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and data from The Cancer Genome Atlas (TCGA) were used for orthogonal validation of selected findings. In unsupervised clustering analysis, the top 500 most variable cytosine-guanine sites segregated SFTs by primary anatomical site. Differentially methylated genes associated with the primary SFT site included EGFR; TBX15; multiple HOX genes; and their cofactors EBF1, EBF3, and PBX1; as well as RUNX1 and MEIS1. Of the 20 DMGs interrogated on the RNA-seq panel, 12 were significantly differentially expressed according to site. However, except TBX15, most of these also showed differential expression according to NAB2::STAT6 fusion type, suggesting that the fusion oncogene contributes to the transcriptional regulation of these genes. Transcriptomic data confirmed an inverse correlation between gene methylation and the expression of TBX15 in both SFT and TCGA sarcomas. TBX15 also showed differential mRNA expression and 5' UTR methylation between tumors in different anatomical sites in TCGA data. In all analyses, TBX15 methylation and mRNA expression retained the strongest association with tissue of origin in SFT and other sarcomas, suggesting a possible marker to distinguish metastatic tumors from new primaries without genomic profiling. Epigenetic signatures may further help to identify SFT progenitor cells at different anatomical sites., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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19. Investigating the Use of Circulating Tumor DNA for Sarcoma Management.
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Darville-O'Quinn P, Gokgoz N, Tsoi KM, Andrulis IL, and Wunder JS
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Background/Objectives : Sarcomas are a heterogeneous group of cancers, many with high rates of recurrence and metastasis, leading to significant morbidity and mortality. Due to a lack of early diagnostic biomarkers, by the time recurrent disease can be clinically detected, it is often extensive and difficult to treat. Here, we sought to investigate methods of detecting ctDNA in sarcoma patient plasma to potentially monitor disease recurrence, progression, and response to treatment. Methods : Whole-exome sequencing of matched tumor and blood samples revealed patient-specific mutations, which were used to develop personalized assays to detect ctDNA in patient plasma. Since ctDNA is present in extremely low quantities, detection requires highly sensitive methodologies. Droplet digital PCR is highly sensitive; however, it is limited in that it can only be used to target one tumor variant at a time. Therefore, a protocol combining multiplex PCR and targeted amplicon sequencing was developed. Results : ddPCR was successfully able to detect tumor-specific mutations in plasma, confirming the presence of ctDNA in sarcoma patients. Multiplex PCR followed by amplicon sequencing was able to detect multiple tumor variants simultaneously, although it was not as sensitive as ddPCR. Additionally, ctDNA was detected in patient plasma collected at two different time points. Conclusions : This work demonstrates that although there is a lack of recurrent biomarkers, personalized assays detecting ctDNA have the potential to be used to monitor disease progression in sarcoma.
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- 2024
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20. Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.
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Rasmussen SV, Wozniak A, Lathara M, Goldenberg JM, Samudio BM, Bickford LR, Nagamori K, Wright H, Woods AD, Chauhan S, Lee CJ, Rudzinski ER, Swift MK, Kondo T, Fisher DE, Imyanitov E, Machado I, Llombart-Bosch A, Andrulis IL, Gokgoz N, Wunder J, Mirotaki H, Nakamura T, Srinivasa G, Thway K, Jones RL, Huang PH, Berlow NE, Schöffski P, and Keller C
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- Child, Adolescent, Young Adult, Humans, Transcriptome, Genomics, Base Sequence, RNA, Oncogene Proteins, Fusion genetics, Sarcoma, Clear Cell genetics, Sarcoma, Clear Cell metabolism, Sarcoma, Clear Cell pathology
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Background: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults., Methods: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines., Results: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability., Conclusion: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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21. Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma.
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Ko A, Coward VS, Gokgoz N, Dickson BC, Tsoi K, Wunder JS, and Andrulis IL
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Sarcomas are a heterogeneous group of mesenchymal neoplasms, many of which are associated with a high risk of metastasis and poor prognosis. Conventional chemotherapy and targeted therapies have varying effects across individuals and tumour subtypes. The current therapies frequently provide limited clinical benefit; hence, more effective treatments are urgently needed. Recent advances in immunotherapy, such as checkpoint inhibition or adoptive cell therapy (ACT), show potential in increasing efficacy by providing a more personalized treatment. Therapy with tumour-infiltrating lymphocytes (TILs) is an emerging field in immunotherapy. Here, we collected 190 sarcoma tumour specimens from patients without pre-operative adjuvant treatment in order to isolate TILs. We compared different methods of TIL expansion and optimized a protocol specifically for efficacy in culturing TILs from sarcoma. The expanded TIL populations were characterized by flow cytometry analysis using CD3, CD4, CD8, CD14, CD19 and CD56 markers. The TIL populations were non-specifically stimulated to establish TIL reactivity. Through an optimized expansion protocol, TILs were isolated and cultured from 54 of 92 primary sarcoma specimens. The isolated TILs varied in CD4
+ and CD8+ T-cell compositions and retained their ability to release IFNγ upon stimulation. Our results suggest that certain sarcoma subtypes have the potential to yield a sufficient number of TILs for TIL therapy.- Published
- 2022
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22. Detection and utility of cell-free and circulating tumour DNA in bone and soft-tissue sarcomas.
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Tsoi KM, Gokgoz N, Darville-O'Quinn P, Prochazka P, Malekoltojari A, Griffin AM, Ferguson PC, Wunder JS, and Andrulis IL
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Aims: Cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) are used for prognostication and monitoring in patients with carcinomas, but their utility is unclear in sarcomas. The objectives of this pilot study were to explore the prognostic significance of cfDNA and investigate whether tumour-specific alterations can be detected in the circulation of sarcoma patients., Methods: Matched tumour and blood were collected from 64 sarcoma patients (n = 70 samples) prior to resection of the primary tumour (n = 57) or disease recurrence (n = 7). DNA was isolated from plasma, quantified, and analyzed for cfDNA. A subset of cases (n = 6) underwent whole exome sequencing to identify tumour-specific alterations used to detect ctDNA using digital droplet polymerase chain reaction (ddPCR)., Results: Cell-free was present in 69 of 70 samples above 0.5 ng/ml. Improved disease-free survival was found for patients with lower cfDNA levels (90% vs 48% at one-year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005). Digital droplet PCR was performed as a pilot study and mutant alleles were detectable at 0.5% to 2.5% of the wild type genome, and at a level of 0.25 ng tumour DNA. Tumour-specific alterations (ctDNA) were found in five of six cases., Conclusion: This work demonstrates the feasibility and potential utility of cfDNA and ctDNA as biomarkers for bone and soft-tissue sarcomas, despite the lack of recurrent genomic alterations. A larger study is required to validate these findings. Cite this article: Bone Joint Res 2021;10(9):602-610.
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- 2021
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23. Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.
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Stocker M, Le Nail LR, De Belenet H, Wunder JS, Andrulis IL, Gokgoz N, Levy N, Mattei JC, and Olschwang S
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Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the MDM2 and CDK4 genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies targeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarcomas., Competing Interests: None., (AJCR Copyright © 2021.)
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- 2021
24. RNA expression profiling reveals PRAME, a potential immunotherapy target, is frequently expressed in solitary fibrous tumors.
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Wang WL, Gokgoz N, Samman B, Andrulis IL, Wunder JS, and Demicco EG
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- Age Factors, Aged, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Female, Humans, Immunotherapy, Male, Middle Aged, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology, Solitary Fibrous Tumors genetics, Solitary Fibrous Tumors pathology, Antigens, Neoplasm metabolism, Soft Tissue Neoplasms metabolism, Solitary Fibrous Tumors metabolism
- Abstract
Solitary fibrous tumors are a type of translocation-associated sarcoma with up to 30% rates of metastasis and poor response to conventional chemotherapy. Other translocation-associated sarcomas have been shown to display elevated expression of various cancer-testis antigens which may render them susceptible to immunotherapy strategies such as cancer vaccines and adoptive T-cell therapy. After an RNA sequencing assay brought the cancer-testis antigen Preferentially Expressed Antigen In Melanoma (PRAME) to our attention as possibly being upregulated in aggressive TERT promoter-mutated solitary fibrous tumors, we used tissue microarrays to asses PRAME expression in a large series of previously characterized solitary fibrous tumors, with correlation to various clinicopathologic features, as well as with tumor-infiltrating macrophages and the associated signal regulatory protein α (SIRPα)-CD47 regulatory checkpoint. We found that PRAME was expressed in 165/180 solitary fibrous tumors, with high expression seen in 58%, irrespective of TERT promoter status. Elevated PRAME expression was more frequent in primary intrathoracic solitary fibrous tumors and correlated with older age at primary diagnosis. Elevated PRAME was also associated with features suggestive of immune evasion, including lower numbers of antigen-presenting CD163+ and CD68+ macrophages, and expression of the "don't eat me" receptor CD47 on tumor cells. Taken together, these features suggest that strategies targeting PRAME with or without concomitant SIRPα-CD47 axis inhibition may represent a potential future therapeutic option in aggressive solitary fibrous tumor.
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- 2021
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25. The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.
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Huang J, Sachdeva M, Xu E, Robinson TJ, Luo L, Ma Y, Williams NT, Lopez O, Cervia LD, Yuan F, Qin X, Zhang D, Owzar K, Gokgoz N, Seto A, Okada T, Singer S, Andrulis IL, Wunder JS, Lazar AJ, Rubin BP, Pipho K, Mello SS, Giudice J, and Kirsch DG
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- Humans, Neoplasm Metastasis, PC-3 Cells, Transfection, RNA Splicing genetics, RNA, Long Noncoding genetics, Sarcoma genetics
- Abstract
Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in Kras and Trp53 (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 ( Neat1 ) is significantly upregulated in lung metastases. Furthermore, NEAT1 RNA ISH of human UPS showed that NEAT1 is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of Neat1 suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA Neat1 promotes sarcoma metastasis, we pulled down Neat1 RNA and used mass spectrometry to identify interacting proteins. Interestingly, most Neat1 interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with Neat1 and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that Neat1 and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis. IMPLICATIONS: Understanding that lncRNA NEAT1 promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma., (©2020 American Association for Cancer Research.)
- Published
- 2020
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26. Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation.
- Author
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Wunder JS, Lee MJ, Nam J, Lau BY, Dickson BC, Pinnaduwage D, Bull SB, Ferguson PC, Seto A, Gokgoz N, and Andrulis IL
- Subjects
- Adult, B7-H1 Antigen genetics, Humans, Bone Neoplasms, Osteosarcoma genetics, Sarcoma genetics, Soft Tissue Neoplasms genetics
- Abstract
Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2020
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27. Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.
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Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, Hajjar S, Layeghifard M, Novokmet A, Kowalski PE, Anaka M, Davidson S, Zarrei M, Id Said B, Schreiner LC, Marchand R, Sitter J, Gokgoz N, Brunga L, Graham GT, Fullam A, Pillay N, Toretsky JA, Yoshida A, Shibata T, Metzler M, Somers GR, Scherer SW, Flanagan AM, Campbell PJ, Schiffman JD, Shago M, Alexandrov LB, Wunder JS, Andrulis IL, Malkin D, Behjati S, and Shlien A
- Subjects
- Adolescent, Bone Neoplasms pathology, Child, DNA Replication, Evolution, Molecular, Female, Genome, Human, Humans, Male, Mutation, Neoplasm Metastasis, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Soft Tissue Neoplasms pathology, Bone Neoplasms genetics, Gene Rearrangement, Oncogene Proteins, Fusion genetics, Sarcoma, Ewing genetics, Soft Tissue Neoplasms genetics
- Abstract
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1 , a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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28. Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients.
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Koster R, Panagiotou OA, Wheeler WA, Karlins E, Gastier-Foster JM, Caminada de Toledo SR, Petrilli AS, Flanagan AM, Tirabosco R, Andrulis IL, Wunder JS, Gokgoz N, Patiño-Garcia A, Lecanda F, Serra M, Hattinger C, Picci P, Scotlandi K, Thomas DM, Ballinger ML, Gorlick R, Barkauskas DA, Spector LG, Tucker M, Belynda DH, Yeager M, Hoover RN, Wacholder S, Chanock SJ, Savage SA, and Mirabello L
- Subjects
- Adult, Alleles, Brazil, Female, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Proportional Hazards Models, Survival Rate, White People genetics, Bone Neoplasms genetics, Bone Neoplasms mortality, Interleukin-33 genetics, Osteosarcoma genetics, Osteosarcoma mortality
- Abstract
Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41-2.18, p = 4.84 × 10
-7 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5-2.4; p = 1.3 × 10-8 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus., (© 2017 UICC.)- Published
- 2018
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29. Identifying actionable variants using next generation sequencing in patients with a historical diagnosis of undifferentiated pleomorphic sarcoma.
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Lewin J, Garg S, Lau BY, Dickson BC, Traub F, Gokgoz N, Griffin AM, Ferguson PC, Andrulis IL, Sim HW, Kamel-Reid S, Stockley TL, Siu LL, Wunder JS, and Razak ARA
- Subjects
- Adult, Aged, Aged, 80 and over, DNA Mutational Analysis methods, DNA, Neoplasm analysis, DNA, Neoplasm genetics, Female, Histiocytoma, Malignant Fibrous mortality, Histiocytoma, Malignant Fibrous pathology, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Soft Tissue Neoplasms mortality, Soft Tissue Neoplasms pathology, High-Throughput Nucleotide Sequencing methods, Histiocytoma, Malignant Fibrous genetics, Soft Tissue Neoplasms genetics
- Abstract
There are limited data regarding the molecular characterization of undifferentiated pleomorphic sarcomas (UPS; formerly malignant fibrous histiocytoma). This study aimed to investigate the utility of next generation sequencing (NGS) in UPS to identify subsets of patients who harbour actionable mutations. Patients diagnosed with UPS underwent pathological re-evaluation by a pathologist specializing in sarcoma. Tumor DNA was isolated from archived fresh frozen tissue samples and genotyped using NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons). In total, 95 patients initially classified with UPS were identified. Following pathology re-review the histological subtypes were reclassified to include: Myxofibrosarcoma (MFS, N = 44); UPS(N = 18); and Others (N = 27; including undifferentiated spindle cell sarcoma (N = 15) and dedifferentiated liposarcoma (N = 6)). Seven cases were excluded from further analysis for other reasons. Baseline demographics of the finalized cohort (N = 88) showed a median age of 66 years (32-95), primarily with stage I-III disease (92%) and high-grade (86%) lesions. Somatic mutations were identified in 31 cases (35%)(Total mutations = 36: solitary mutation(n = 27); two mutations( =n = 3); three mutations(n = 1)). The most commonly identified mutations were in TP53 (n = 24), ATM (n = 3) and PIK3CA (n = 2). Three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, mainly related to biomarkers of prediction of response; however few had targetable driver mutations. Somatic mutation status did not influence disease free or overall survival. Based on the small number of clinically relevant mutations, these data do not support the routine use of targeted NGS panels outside of research protocols in UPS., (© 2017 UICC.)
- Published
- 2018
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30. Response of Escherichia coli to Prolonged Berberine Exposure.
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Budeyri Gokgoz N, Avci FG, Yoneten KK, Alaybeyoglu B, Ozkirimli E, Sayar NA, Kazan D, and Sariyar Akbulut B
- Subjects
- Bacterial Outer Membrane Proteins agonists, Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins metabolism, Biological Transport drug effects, Cell Division drug effects, Drug Resistance, Bacterial genetics, Escherichia coli K12 genetics, Escherichia coli K12 metabolism, Escherichia coli K12 ultrastructure, Escherichia coli Proteins agonists, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Gene Expression Profiling, Gene Ontology, Metabolic Networks and Pathways drug effects, Metabolic Networks and Pathways genetics, Molecular Sequence Annotation, Proteome metabolism, Time Factors, Anti-Bacterial Agents pharmacology, Berberine pharmacology, Escherichia coli K12 drug effects, Gene Expression Regulation, Bacterial drug effects, Protein Biosynthesis drug effects, Proteome genetics
- Abstract
Berberine is a plant-derived alkaloid possessing antimicrobial activity; unfortunately, its efflux through multidrug resistance pumps reduces its efficacy. Cellular life span of Escherichia coli is generally shorter with prolonged berberine exposure; nevertheless, about 30% of the cells still remain robust following this treatment. To elucidate its mechanism of action and to identify proteins that could be involved in development of antimicrobial resistance, protein profiles of E. coli cells treated with berberine for 4.5 and 8 hours were compared with control cells. A total of 42 proteins were differentially expressed in cells treated with berberine for 8 hours when compared to control cells. In both 4.5 and 8 hours of berberine-treated cells, carbohydrate and peptide uptake regimens remained unchanged, although amino acid maintenance regimen switched from transport to synthesis. Defect in cell division persisted and this condition was confirmed by images obtained from scanning electron microscopy. Universal stress proteins were not involved in stress response. The significant increase in the abundance of elongation factors could suggest the involvement of these proteins in protection by exhibiting chaperone activities. Furthermore, the involvement of the outer membrane protein OmpW could receive special attention as a protein involved in response to antimicrobial agents, since the expression of only this porin protein was upregulated after 8 hours of exposure.
- Published
- 2017
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31. Right-sided lateralization of skin temperature in healthy young persons.
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Demirel H, Bahar A, Gokgoz N, Arslan M, and Dane S
- Subjects
- Adolescent, Adult, Female, Humans, Male, Lymph Nodes physiology, Skin Temperature physiology
- Abstract
Purpose: Previous studies reported a peripheral immune asymmetry and lateralization of different paired organ cancers. Because of the close relationship of immune system with body temperature, the aim of the study was to test the possible lateralization of skin temperature., Materials and Methods: Four hundred sixty three healthy subjects (325 women, 138 men) with an average age of 23.62 years (SD = 8.65) participated in this study. All skin temperature measurements were done 8:00-9:00 a.m. Skin temperature was assessed for three different points in skin: axillary, thumb and external auditory., Results: Skin temperature was statistically significantly higher on the right side of the body than on the left side, when measured by axillary and thumb temperatures. But there was no statistically significant difference in external auditory temperature., Conclusion: The asymmetry of skin temperature may result from the peripheral immune asymmetry or the asymmetric lymph node distribution.
- Published
- 2016
32. The genomic landscape of epithelioid sarcoma cell lines and tumours.
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Jamshidi F, Bashashati A, Shumansky K, Dickson B, Gokgoz N, Wunder JS, Andrulis IL, Lazar AJ, Shah SP, Huntsman DG, and Nielsen TO
- Subjects
- Blotting, Western, Cell Line, Tumor, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Gene Knockdown Techniques, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Immunoprecipitation, In Situ Hybridization, Fluorescence, Multiplex Polymerase Chain Reaction, Polymerase Chain Reaction, RNA, Small Interfering, SMARCB1 Protein, Tissue Array Analysis, Transcription Factors genetics, Transfection, Sarcoma genetics, Transcriptome
- Abstract
We carried out whole genome and transcriptome sequencing on four tumour/normal pairs of epithelioid sarcoma. These index cases were supplemented with whole transcriptome sequencing of three additional tumours and three cell lines. Unlike rhabdoid tumour (the other major group of SMARCB1-negative cancers), epithelioid sarcoma shows a complex genome with a higher mutational rate, comparable to that of ovarian carcinoma. Despite this mutational burden, SMARCB1 mutations remain the most frequently recurring event and are probably critical drivers of tumour formation. Several cases show heterozygous SMARCB1 mutations without inactivation of the second allele, and we explore this further in vitro. Finding CDKN2A deletions in our discovery cohort, we evaluated CDKN2A protein expression in a tissue microarray. Six out of 16 cases had lost CDKN2A in greater than or equal to 90% of cells, while the remaining cases had retained the protein. Expression analysis of epithelioid sarcoma cell lines by transcriptome sequencing shows a unique profile that does not cluster with any particular tissue type or with other SWI/SNF-aberrant lines. Evaluation of the levels of members of the SWI/SNF complex other than SMARCB1 revealed that these proteins are expressed as part of a residual complex, similarly to previously studied rhabdoid tumour lines. This residual SWI/SNF is susceptible to synthetic lethality and may therefore indicate a therapeutic opportunity., (Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2016
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33. Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.
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Wong P, Hui A, Su J, Yue S, Haibe-Kains B, Gokgoz N, Xu W, Bruce J, Williams J, Catton C, Wunder JS, Andrulis IL, Gladdy R, Dickson B, O'Sullivan B, and Liu FF
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Cell Adhesion physiology, Cell Line, Tumor, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Sarcoma enzymology, Sarcoma pathology, Transfection, rho-Associated Kinases metabolism, MicroRNAs genetics, Sarcoma genetics, rho-Associated Kinases genetics
- Abstract
A common and aggressive subtype of soft-tissue sarcoma, undifferentiated pleomorphic sarcoma (UPS) was examined to determine the role of micro-RNAs (miRNAs) in modulating distant metastasis. Following histopathologic review, 110 fresh frozen clinically annotated UPS samples were divided into two independent cohorts for Training (42 patients), and Validation (68 patients) analyses. Global miRNA profiling on the Training Set and functional analysis in vitro suggested that miRNA-138 and its downstream RHO-ROCK cell adhesion pathway was a convergent target of miRNAs associated with the development of metastasis. A six-miRNA signature set prognostic of distant metastasis-free survival (DMFS) was developed from Training Set miRNA expression values. Using the six-miRNA signature, patients were successfully categorized into high- and low-risk groups for DMFS in an independent Validation Set, with a hazard ratio (HR) of 2.25 (p = 0.048). After adjusting for other known prognostic variables such as age, gender, tumor grade, size, depth, and treatment with radiotherapy, the six-miRNA signature retained prognostic value with a HR of 3.46 (p < 0.001). A prognostic miRNA biomarker for clinical validation was thus identified along with a functional pathway that modulates UPS metastatic phenotype.
- Published
- 2015
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34. A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.
- Author
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Mirabello L, Koster R, Moriarity BS, Spector LG, Meltzer PS, Gary J, Machiela MJ, Pankratz N, Panagiotou OA, Largaespada D, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, de Toledo SR, Petrilli AS, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Andrulis IL, Wunder JS, Gokgoz N, Serra M, Hattinger C, Picci P, Scotlandi K, Flanagan AM, Tirabosco R, Amary MF, Halai D, Ballinger ML, Thomas DM, Davis S, Barkauskas DA, Marina N, Helman L, Otto GM, Becklin KL, Wolf NK, Weg MT, Tucker M, Wacholder S, Fraumeni JF Jr, Caporaso NE, Boland JF, Hicks BD, Vogt A, Burdett L, Yeager M, Hoover RN, Chanock SJ, and Savage SA
- Subjects
- Alleles, Animals, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Chromosomes, Human, Pair 9, DNA Transposable Elements, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Mice, Mutagenesis, Insertional, Neoplasm Metastasis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Bone Neoplasms genetics, Bone Neoplasms pathology, Genetic Variation, Genome-Wide Association Study, NFI Transcription Factors genetics, Osteosarcoma genetics, Osteosarcoma pathology
- Abstract
Unlabelled: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10(-9); OR, 2.43; 95% confidence interval, 1.83-3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene., Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma., (©2015 American Association for Cancer Research.)
- Published
- 2015
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35. Germline TP53 variants and susceptibility to osteosarcoma.
- Author
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Mirabello L, Yeager M, Mai PL, Gastier-Foster JM, Gorlick R, Khanna C, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Andrulis IL, Wunder JS, Gokgoz N, Barkauskas DA, Zhang X, Vogt A, Jones K, Boland JF, Chanock SJ, and Savage SA
- Subjects
- Adult, Age of Onset, Female, Genetic Predisposition to Disease, Humans, Li-Fraumeni Syndrome genetics, Male, Bone Neoplasms genetics, Germ-Line Mutation, Osteosarcoma genetics, Tumor Suppressor Protein p53 genetics
- Abstract
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
- Published
- 2015
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36. Aberrant hedgehog signaling and clinical outcome in osteosarcoma.
- Author
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Lo WW, Pinnaduwage D, Gokgoz N, Wunder JS, and Andrulis IL
- Abstract
Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration.
- Published
- 2014
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37. Genome-wide association study identifies two susceptibility loci for osteosarcoma.
- Author
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Savage SA, Mirabello L, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, Flanagan AM, Tirabosco R, Andrulis IL, Wunder JS, Gokgoz N, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Kurucu N, Ilhan IE, Sari N, Serra M, Hattinger C, Picci P, Spector LG, Barkauskas DA, Marina N, de Toledo SR, Petrilli AS, Amary MF, Halai D, Thomas DM, Douglass C, Meltzer PS, Jacobs K, Chung CC, Berndt SI, Purdue MP, Caporaso NE, Tucker M, Rothman N, Landi MT, Silverman DT, Kraft P, Hunter DJ, Malats N, Kogevinas M, Wacholder S, Troisi R, Helman L, Fraumeni JF Jr, Yeager M, Hoover RN, and Chanock SJ
- Subjects
- Adolescent, Adult, Bone Neoplasms ethnology, Case-Control Studies, Female, Humans, Linkage Disequilibrium, Male, Osteosarcoma ethnology, Polymorphism, Single Nucleotide, White People genetics, Young Adult, Bone Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Osteosarcoma genetics
- Abstract
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
- Published
- 2013
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38. Protein kinase C epsilon and genetic networks in osteosarcoma metastasis.
- Author
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Goudarzi A, Gokgoz N, Gill M, Pinnaduwage D, Merico D, Wunder JS, and Andrulis IL
- Abstract
Osteosarcoma (OS) is the most common primary malignant tumor of the bone, and pulmonary metastasis is the most frequent cause of OS mortality. The aim of this study was to discover and characterize genetic networks differentially expressed in metastatic OS. Expression profiling of OS tumors, and subsequent supervised network analysis, was performed to discover genetic networks differentially activated or organized in metastatic OS compared to localized OS. Broad trends among the profiles of metastatic tumors include aberrant activity of intracellular organization and translation networks, as well as disorganization of metabolic networks. The differentially activated PRKCε-RASGRP3-GNB2 network, which interacts with the disorganized DLG2 hub, was also found to be differentially expressed among OS cell lines with differing metastatic capacity in xenograft models. PRKCε transcript was more abundant in some metastatic OS tumors; however the difference was not significant overall. In functional studies, PRKCε was not found to be involved in migration of M132 OS cells, but its protein expression was induced in M112 OS cells following IGF-1 stimulation.
- Published
- 2013
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39. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma.
- Author
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Mejia-Guerrero S, Quejada M, Gokgoz N, Gill M, Parkes RK, Wunder JS, and Andrulis IL
- Subjects
- Adult, Aged, Bone Neoplasms diagnosis, Bone Neoplasms metabolism, Child, Child, Preschool, Chromosome Mapping, Cyclin-Dependent Kinase 4 biosynthesis, Female, Gene Amplification, Gene Expression, Genes, p53, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Osteosarcoma diagnosis, Osteosarcoma metabolism, Prognosis, Proto-Oncogene Proteins c-mdm2 biosynthesis, Young Adult, Bone Neoplasms genetics, Chromosomes, Human, Pair 12, Cyclin-Dependent Kinase 4 genetics, Osteosarcoma genetics, Proto-Oncogene Proteins c-mdm2 genetics
- Abstract
The chromosomal region 12q13-15 is recurrently amplified in osteosarcoma (OS), but its importance in bone tumor development remains unknown. Although there are two major candidate genes (MDM2, a TP53 downregulator, and CDK4, involved in cell cycle progression) considered to be the driving genes in this region, the size of the amplicon and number of genes involved have not been determined. In this study, we used 130 classical OS and 15 parosteal OS to determine MDM2 and CDK4 amplification frequency in OS. Tumors in which these genes were amplified were used to map the 12q13-15 amplified region and to determine its correlation with clinical prognosis. The 12q13-15 amplification was more prevalent in parosteal OS (67% of cases) than in high-grade classical OS (12%). Quantitative real-time PCR of MDM2, CDK4, and 25 other genes showed that this region contains two different amplicons: one at 12q15 centered on MDM2 and one at 12q13-14 centered on CDK4. Both regions were frequently co-amplified in both types of OS, and MDM2 and CDK4 amplification was correlated with higher expression levels for both genes. Univariate and multivariate analyses of clinical data indicated that classical OS patients whose tumors exhibited MDM2 amplification were more likely to be older at diagnosis (median age 32.6 vs. 17.8 years) and female (66.7 vs. 33.3%) than those without gene amplification. There was no association with other clinical parameters. In conclusion, co-amplification of MDM2 and CDK4 in two separate amplicons occurs frequently in parosteal OS and less so in classical high-grade OS., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
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40. COPS3 amplification and clinical outcome in osteosarcoma.
- Author
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Yan T, Wunder JS, Gokgoz N, Gill M, Eskandarian S, Parkes RK, Bull SB, Bell RS, and Andrulis IL
- Subjects
- Adolescent, Adult, Aged, Bone Neoplasms mortality, Bone Neoplasms pathology, COP9 Signalosome Complex, Child, Preschool, Female, Humans, Intracellular Signaling Peptides and Proteins, Kaplan-Meier Estimate, Male, Middle Aged, Myelin Proteins genetics, Nuclear Proteins genetics, Nuclear Receptor Co-Repressor 1, Osteosarcoma mortality, Osteosarcoma pathology, Polymorphism, Single-Stranded Conformational, Prognosis, Proteins genetics, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53 genetics, Bone Neoplasms genetics, Gene Amplification, Osteosarcoma genetics, Proto-Oncogene Proteins genetics
- Abstract
Background: Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high-grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high-grade osteosarcoma and long-term clinical follow-up were examined., Methods: Quantitative real-time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups., Results: Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P=.0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02-2.55) in univariate analysis (log-rank test, P=.042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82-2.13, P=.25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone., Conclusions: COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis., (Copyright (c) 2007 American Cancer Society)
- Published
- 2007
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41. hCDC4 variation in osteosarcoma.
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Yan T, Wunder JS, Gokgoz N, Seto KK, Bell RS, and Andrulis IL
- Subjects
- Cell Line, Tumor, F-Box-WD Repeat-Containing Protein 7, Humans, Mutation, Polymorphism, Single-Stranded Conformational, Sequence Analysis, DNA methods, Aneuploidy, Cell Cycle Proteins genetics, F-Box Proteins genetics, Osteosarcoma genetics, Ubiquitin-Protein Ligases genetics
- Abstract
The hCDC4 gene (also known as Fbw7 or Archipelago) encodes an F-box protein that is responsible for targeting cyclin E for Skp1-cullin-F box protein (SCF) ubiquitination and proteosomal degradation. Disruption of this pathway has been associated with chromosomal instability and aneuploidy in several cancer cell lines and primary tumors. This study aimed to examine whether hCDC4 mutations contribute to aneuploidy in osteosarcoma. We analyzed 147 primary high-grade osteosarcoma specimens and 6 osteosarcoma cell lines. The protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) analysis with subsequent sequencing were performed to detect alterations of the hCDC4 gene. All specimens exhibited the same PTT pattern of normal bands with less intense common bands. Two shifts were detected by SSCP, and subsequent DNA analysis identified one in-frame three-base GAG (424-426) deletion and one silent nucleotide substitution (C1261T). We conclude that somatic hCDC4 mutations are infrequent in osteosarcoma, and are unlikely to play an important role in aneuploidy of this tumor.
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- 2006
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42. Application of reliability coefficients in cDNA microarray data analysis.
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He W, Bull SB, Gokgoz N, Andrulis I, and Wunder J
- Subjects
- Computer Simulation, Humans, Reproducibility of Results, Sarcoma genetics, Soft Tissue Neoplasms genetics, Data Interpretation, Statistical, Models, Statistical, Oligonucleotide Array Sequence Analysis methods
- Abstract
Gene expression microarray technology has been widely used in areas such as human cancer research to identify molecular characteristics of sample specimens. The microarray study, however, is a very complicated procedure which involves numerous sources of variability that may be either systematic or random. Systematic variation is often eliminated by applying normalization procedures, but at present there are no standard criteria available to evaluate the performance of a particular normalization approach. In this paper, we propose a reliability-type coefficient as a criterion to assess the effectiveness of normalization procedures in eliminating systematic variation. Simulation studies show that this criterion performs reasonably well in a range of settings. The proposed method is illustrated using a subset of an ongoing microarray study of soft-tissue sarcoma., (Copyright (c) 2005 John Wiley & Sons, Ltd.)
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- 2006
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43. Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation.
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Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Alman BA, and Wunder JS
- Subjects
- Animals, DNA Mutational Analysis, Hedgehog Proteins, Humans, Hypolipidemic Agents pharmacology, Immunohistochemistry, Mice, Mice, Inbred NOD, Mice, SCID, Oncogene Proteins biosynthesis, Organ Culture Techniques, Parathyroid Hormone-Related Protein genetics, Patched Receptors, Patched-1 Receptor, Polymorphism, Single-Stranded Conformational, Receptors, Cell Surface biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Trans-Activators drug effects, Transcription Factors biosynthesis, Triparanol pharmacology, Up-Regulation, Zinc Finger Protein GLI1, Bone Neoplasms metabolism, Cell Proliferation drug effects, Chondrosarcoma metabolism, Parathyroid Hormone-Related Protein metabolism, Signal Transduction physiology, Trans-Activators metabolism
- Abstract
Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.
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- 2006
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44. LAF-4 is aberrantly expressed in human breast cancer.
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To MD, Faseruk SA, Gokgoz N, Pinnaduwage D, Done SJ, and Andrulis IL
- Subjects
- Breast pathology, Breast physiopathology, Breast Neoplasms pathology, Breast Neoplasms surgery, DNA Methylation, DNA, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Menopause, Promoter Regions, Genetic, Proto-Oncogene Mas, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic, Tumor Cells, Cultured, Breast Neoplasms genetics, Nuclear Proteins genetics
- Abstract
LAF-4, which encodes a nuclear protein with transactivation potential, is fused to the MLL gene in acute lymphoblastic leukemia (ALL). We identified LAF-4 as a gene that is transcriptionally deregulated in breast tumors and thus may have a pathological role in mammary tumorigenesis. In line with the previous finding that LAF-4 expression is tissue specific, we did not detect any LAF-4 mRNA in normal mammary epithelial cell lines. However, 2 of 5 breast cancer cell lines were found to express LAF-4 at both the RNA and protein levels. In 2 of 9 primary tumor-normal pairs, the expression of LAF-4 was clearly elevated in the tumor tissue. Using RNA in situ hybridization, we demonstrated that LAF-4 is expressed in mammary tumor cells but not in normal acini. In a group of 64 primary human breast tumors, we found that LAF-4 was overexpressed in approximately 20% of the cases. Although epigenetic changes may be involved in altered expression of some genes, differences in LAF-4 expression were not associated with DNA methylation of the predicted promoter region. Our results suggest that LAF-4 may be a proto-oncogene that is transcriptionally activated in some cases of breast cancer., (Copyright 2005 Wiley-Liss, Inc.)
- Published
- 2005
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45. TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.
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Wunder JS, Gokgoz N, Parkes R, Bull SB, Eskandarian S, Davis AM, Beauchamp CP, Conrad EU, Grimer RJ, Healey JH, Malkin D, Mangham DC, Rock MJ, Bell RS, and Andrulis IL
- Subjects
- Adolescent, Adult, Biomarkers, Tumor analysis, Blotting, Southern, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Bone Neoplasms therapy, Humans, Osteosarcoma drug therapy, Osteosarcoma genetics, Osteosarcoma therapy, Prospective Studies, Treatment Outcome, Bone Neoplasms diagnosis, Genes, p53 genetics, Mutation, Osteosarcoma diagnosis
- Abstract
Purpose: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma., Patients and Methods: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors., Results: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome., Conclusion: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.
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- 2005
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46. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.
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Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, Karp JE, Gokgoz N, Wunder JS, Andrulis IL, Levine AJ, Mankowski JL, and Baylin SB
- Subjects
- Animals, Chromosome Deletion, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Methylation, Genes, Tumor Suppressor, Heterozygote, Humans, Immunohistochemistry, Kruppel-Like Transcription Factors, Mice, Mice, Knockout, Mutation genetics, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Osteosarcoma genetics, Osteosarcoma pathology, Phenotype, Promoter Regions, Genetic, Transcription Factors metabolism, Tumor Suppressor Protein p53 deficiency, Tumor Suppressor Protein p53 genetics, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Epigenesis, Genetic genetics, Transcription Factors deficiency, Transcription Factors genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
The gene hypermethylated in cancer 1 (HIC1) is epigenetically inactivated, but not mutated, in cancer. Here we show that cooperative loss of Hic1 with p53, but not INK4a, yields distinct tumor phenotypes in mice. Germline deletion of one allele of each gene on the opposite chromosome yields breast and ovarian carcinomas and metastatic osteosarcomas with epigenetic inactivation of the wild-type Hic1 allele. Germline deletion of the two genes on the same chromosome results in earlier appearance and increased prevalence and aggressiveness of osteosarcomas with genetic deletion of both wild-type genes. In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutations. Our results indicate the importance of genes altered only through epigenetic mechanisms in cancer progression in conjunction with genetically modified tumor suppressor genes.
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- 2004
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47. Cloning and mutation analysis of ZFP276 as a candidate tumor suppressor in breast cancer.
- Author
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Wong JCY, Gokgoz N, Alon N, Andrulis IL, and Buchwald M
- Subjects
- Alleles, Amino Acid Sequence, Blotting, Northern, Breast Neoplasms pathology, Chromosomes, Human, Pair 16, Cloning, Molecular, DNA Mutational Analysis, DNA, Complementary metabolism, Female, Humans, Models, Genetic, Molecular Sequence Data, Nuclear Proteins, Polymorphism, Single-Stranded Conformational, RNA, Messenger metabolism, Sequence Homology, Amino Acid, Zinc Fingers, Breast Neoplasms genetics, Genes, Tumor Suppressor, Polymorphism, Genetic, Tumor Suppressor Proteins genetics
- Abstract
Loss of heterozygosity (LOH) involving chromosome 16q23.4 occurs frequently in breast tumors, which suggests that this region may contain a tumor suppressor gene. Since ZFP276 is located in this region, we have therefore cloned and performed mutation analysis of its coding region in 70 breast tumors. One silent polymorphism and two alterations predicted to result in amino acid changes were detected. Absence of the wild-type allele in tumors carrying the E530D variant suggests a possible role for this change in tumorigenesis.
- Published
- 2003
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48. A mutant PTH/PTHrP type I receptor in enchondromatosis.
- Author
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Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Jüppner H, Andrulis IL, Wunder JS, and Alman BA
- Subjects
- Animals, Bone Neoplasms genetics, COS Cells, Enchondromatosis genetics, Hedgehog Proteins, Humans, Mice, Mice, Transgenic, Mutagenesis, Site-Directed, Receptor, Parathyroid Hormone, Type 1, Receptors, Parathyroid Hormone genetics, Receptors, Parathyroid Hormone metabolism, Second Messenger Systems, Signal Transduction, Trans-Activators metabolism, Bone Neoplasms physiopathology, Enchondromatosis physiopathology, Mutation, Receptors, Parathyroid Hormone physiology
- Abstract
Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.
- Published
- 2002
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49. Screening of deletions in SMN, NAIP and BTF2p44 genes in Turkish spinal muscular atrophy patients.
- Author
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Savas S, Gokgoz N, Kayserili H, Ozkinay F, Yuksel-Apak M, and Kirdar B
- Subjects
- Chromosomes, Human, Pair 5, Cyclic AMP Response Element-Binding Protein, Exons, Genetic Testing, Genotype, Humans, Models, Genetic, Neuronal Apoptosis-Inhibitory Protein, Phenotype, RNA-Binding Proteins, SMN Complex Proteins, Survival of Motor Neuron 1 Protein, Turkey, Gene Deletion, Muscular Atrophy, Spinal genetics, Nerve Tissue Proteins genetics
- Abstract
Deletions of the spinal muscular atrophy (SMA)-determining gene, SMN1, NAIP, and a third multicopy gene, BTF2p44tel were investigated in 60 unrelated Turkish SMA patients. SMN1 was deleted for at least exons 7 and 8 in 85% of the Turkish SMA patients. The NAIP gene was deleted in 75 and 33% of type I and type II SMA patients, respectively. Analysis of the 5'end of the BTF2p44tel gene indicated the extension of deletion in 13.3% of the cases, mainly in type I patients. Deletions of the NAIP and BTF2p44tel genes were detected in 1.3 and 3.9% of carrriers, respectively, in Turkish SMA families. Two patients were detected to harbor the hybrid SMN gene, one type II with deletion of the NAIP gene, and one type III without deletion of the NAIP gene., (Copyright 2000 S. Karger AG, Basel.)
- Published
- 2000
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50. Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.
- Author
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Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, and Rutka JT
- Subjects
- Age of Onset, Alleles, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosomes, Human, Pair 22 genetics, Conserved Sequence genetics, Exons genetics, Female, Frameshift Mutation genetics, Genes, Dominant genetics, Genes, Tumor Suppressor genetics, Genetic Predisposition to Disease genetics, Humans, Infant, Infratentorial Neoplasms epidemiology, Infratentorial Neoplasms pathology, Loss of Heterozygosity genetics, Lymphocytes metabolism, Male, Pedigree, Penetrance, RNA Splicing genetics, Regulatory Sequences, Nucleic Acid genetics, Rhabdoid Tumor epidemiology, Rhabdoid Tumor pathology, SMARCB1 Protein, DNA-Binding Proteins genetics, Germ-Line Mutation genetics, Infratentorial Neoplasms genetics, Rhabdoid Tumor genetics, Transcription Factors genetics
- Abstract
We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy.
- Published
- 2000
- Full Text
- View/download PDF
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