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1. Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

Author

Rokita, JL, Rathi, KS, Cardenas, MF, Upton, KA, Jayaseelan, J, Cross, KL, Pfeil, J, Egolf, LE, Way, GP, Farrel, A, Kendsersky, NM, Patel, K, Gaonkar, KS, Modi, A, Berko, ER, Lopez, G, Vaksman, Z, Mayoh, C, Nance, J, McCoy, K, Haber, M, Evans, K, McCalmont, H, Bendak, K, Böhm, JW, Marshall, GM, Tyrrell, V, Kalletla, K, Braun, FK, Qi, L, Du, Y, Zhang, H, Lindsay, HB, Zhao, S, Shu, J, Baxter, P, Morton, C, Kurmashev, D, Zheng, S, Chen, Y, Bowen, J, Bryan, AC, Leraas, KM, Coppens, SE, Doddapaneni, HV, Momin, Z, Zhang, W, Sacks, GI, Hart, LS, Krytska, K, Mosse, YP, Gatto, GJ, Sanchez, Y, Greene, CS, Diskin, SJ, Vaske, OM, Haussler, D, Gastier-Foster, JM, Kolb, EA, Gorlick, R, Li, XN, Reynolds, CP, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, Raman, P, Wheeler, DA, Maris, JM, Rokita, JL, Rathi, KS, Cardenas, MF, Upton, KA, Jayaseelan, J, Cross, KL, Pfeil, J, Egolf, LE, Way, GP, Farrel, A, Kendsersky, NM, Patel, K, Gaonkar, KS, Modi, A, Berko, ER, Lopez, G, Vaksman, Z, Mayoh, C, Nance, J, McCoy, K, Haber, M, Evans, K, McCalmont, H, Bendak, K, Böhm, JW, Marshall, GM, Tyrrell, V, Kalletla, K, Braun, FK, Qi, L, Du, Y, Zhang, H, Lindsay, HB, Zhao, S, Shu, J, Baxter, P, Morton, C, Kurmashev, D, Zheng, S, Chen, Y, Bowen, J, Bryan, AC, Leraas, KM, Coppens, SE, Doddapaneni, HV, Momin, Z, Zhang, W, Sacks, GI, Hart, LS, Krytska, K, Mosse, YP, Gatto, GJ, Sanchez, Y, Greene, CS, Diskin, SJ, Vaske, OM, Haussler, D, Gastier-Foster, JM, Kolb, EA, Gorlick, R, Li, XN, Reynolds, CP, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, Raman, P, Wheeler, DA, and Maris, JM

Abstract

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.

Published
2019

2. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Author

Lazar, AJ, McLellan, MD, Bailey, MH, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Fulton, RS, Mardis, ER, Schmidt, HK, Wong, W, Wilson, RK, Yellapantula, V, Radenbaugh, AJ, Hoadley, KA, Hayes, DN, Parker, JS, Wilkerson, MD, Auman, JT, Balu, S, Bodenheimer, T, Hoyle, AP, Jefferys, SR, Jones, CD, Lehmann, K-V, Meng, S, Mieczkowski, PA, Mose, LE, Perou, CM, Roach, J, Senbabaoglu, Y, Shi, Y, Simons, JV, Skelly, T, Soloway, MG, Tan, D, Veluvolu, U, Davis, IJ, Hepperla, AJ, Brohl, AS, Kasaian, K, Mungall, K, Sadeghi, S, Barthel, FP, Verhaak, R, Hu, X, Chibon, F, Cherniack, AD, Shih, J, Beroukhim, R, Meyerson, M, Cibulskis, C, Gabriel, SB, Saksena, G, Schumacher, SE, Gao, Q, Wyczalkowski, M, Bowlby, R, Robertson, AG, Ally, A, Balasundaram, M, Brooks, D, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Li, I, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Danilova, L, Cope, L, Baylin, SB, Bootwalla, MS, Lai, PH, Laird, PW, Maglinte, DT, Van Den Berg, DJ, Weisenberger, DJ, Wrangle, J, Drill, E, Shen, R, Iype, L, Reynolds, SM, Shmulevich, I, Yau, C, Armenia, J, Liu, EM, Benz, C, Pastore, A, Sanchez-Vega, F, Schultz, N, Akbani, R, Hegde, AM, Liu, W, Lu, Y, Mills, GB, Weinstein, JN, Roszik, J, Anur, P, Spellman, P, Abeshouse, A, Chen, H-W, Gao, J, Heins, Z, Kundra, R, Larsson, E, Ochoa, A, Sander, C, Socci, N, Zhang, H, Noble, MS, Heiman, DI, Kim, J, Chin, L, Getz, G, Cho, J, Defreitas, T, Frazer, S, Gehlenborg, N, Lawrence, MS, Lin, P, Meier, S, Voet, D, Byers, L, Diao, L, Gay, CM, Wang, J, Newton, Y, Cooper, LAD, Gutman, DA, Lee, S, Nalisnik, M, Bowen, J, Gastier-Foster, JM, Gerken, M, Helsel, C, Hobensack, S, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Anderson, ML, Castro, P, Ittmann, M, Gordienko, E, Paklina, O, Setdikova, G, Raut, CP, Karlan, BY, Lester, J, Belyaev, D, Fulidou, V, Potapova, O, Voronina, O, Demetri, GD, Ramalingam, SS, Behera, M, Delman, K, Owonikoko, TK, Sica, GL, Boyd, J, Magliocco, A, Salner, A, Bennett, J, Iacocca, M, Swanson, P, Dottino, P, Kalir, T, Pereira, E, Akeredolu, T, Crain, D, Curley, E, Gardner, J, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Thompson, E, Hoon, DB, Parfitt, J, Birrer, M, Karseladze, A, Mariamidze, A, Dao, F, Levine, DA, Olvera, N, Maki, RG, Bartlett, J, Eschbacher, J, Dubina, M, Mozgovoy, E, Fedosenko, K, Manikhas, G, Sekhon, H, Ramirez, N, Ingram, DR, Torres, KE, DiSaia, P, Godwin, AK, Godwin, EM, Kuo, H, Madan, R, Reilly, C, Adebamowo, C, Adebamowo, SN, Bocklage, T, Higgins, K, Martinez, C, Boice, L, Grilley-Olson, JE, Huang, M, Perou, AH, Thorne, LB, Rathmell, WK, Gutmann, DH, Singer, S, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Felau, I, Zenklusen, JC, Demchok, JA, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zhang, JJ, Demicco, EG, Doyle, LA, Hornick, JL, Rubin, BP, de Rijn, MV, Baker, L, Riedel, RF, Ding, L, Ladanyi, M, Novak, JE, Van Tine, BA, Davis, LE, Grilley-Olsen, JE, Pollock, RE, Jones, KB, Martignetti, JA, Tong, P, and Network, CGAR

Subjects
0301 basic medicine, Leiomyosarcoma, Adult, Epigenomics, DNA Copy Number Variations, Genomics, Biology, General Biochemistry, Genetics and Molecular Biology, Undifferentiated Pleomorphic Sarcoma, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Cluster Analysis, Humans, ATRX, Aged, Comparative genomics, Aged, 80 and over, Genome, Human, Sarcoma, Middle Aged, medicine.disease, Synovial sarcoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, DNA methylation, Mutation, Cancer research, Genome-Wide Association Study
Abstract

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes ( TP53 , ATRX , RB1 ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Published
2017
Full Text
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3. Integrated genomic characterization of oesophageal carcinoma

Author

Kim, J, Bowlby, R, Mungall, AJ, Robertson, AG, Odze, RD, Cherniack, AD, Shih, J, Pedamallu, CS, Cibulskis, C, Dunford, A, Meier, SR, Raphael, BJ, Wu, H-T, Wong, AM, Willis, JE, Bass, AJ, Derks, S, Garman, K, McCall, SJ, Wiznerowicz, M, Pantazi, A, Parfenov, M, Thorsson, V, Shmulevich, I, Dhankani, V, Miller, M, Sakai, R, Wang, K, Schultz, N, Shen, R, Arora, A, Weinhold, N, Sanchez-Vega, F, Kelsen, DP, Zhang, J, Felau, I, Demchok, J, Rabkin, CS, Camargo, MC, Zenklusen, JC, Bowen, J, Leraas, K, Lichtenberg, TM, Curtis, C, Seoane, JA, Ojesina, AI, Beer, DG, Gulley, ML, Pennathur, A, Luketich, JD, Zhou, Z, Weisenberger, DJ, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Zhang, W, Reid, BJ, Hinoue, T, Laird, PW, Shen, H, Piazuelo, MB, Schneider, BG, McLellan, M, Taylor-Weiner, A, Lawrence, M, Cibulskis, K, Stewart, C, Getz, G, Lander, E, Gabriel, SB, Ding, L, McLellan, MD, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Mardis, ER, Wilson, RK, Schmidt, HK, Fulton, RS, Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Kasaian, K, Brooks, D, Li, HI, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, KL, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Beroukhim, R, Bullman, S, Murray, BA, Saksena, G, Schumacher, SE, Gabriel, S, Meyerson, M, Hadjipanayis, A, Kucherlapati, R, Ren, X, Park, PJ, Lee, S, Kucherlapati, M, Yang, L, Baylin, SB, Hoadley, KA, Bootwalla, MS, Lai, PH, Van den Berg, DJ, Berrios, M, Holbrook, A, Hwang, J-E, Jang, H-J, Weinstein, JN, Lu, Y, Sohn, BH, Mills, G, Seth, S, Protopopov, A, Bristow, CA, Mahadeshwar, HS, Tang, J, Song, X, Cho, J, Defrietas, T, Frazer, S, Gehlenborg, N, Heiman, DI, Lawrence, MS, Lin, P, Noble, MS, Doug, V, Zhang, H, Polak, P, Chin, L, Bernard, B, Iype, L, Reynolds, SM, Abeshouse, A, Armenia, J, Kundra, R, Ladanyi, M, Kjong-Van, L, Gao, J, Sander, C, Chakravarty, D, Radenbaugh, A, Hegde, A, Penny, R, Crain, D, Gardner, J, Curley, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Frick, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Ramirez, NC, Wise, L, Zmuda, E, Tarvin, K, Saller, C, Park, YS, Button, M, Carvalho, AL, Reis, RM, Matsushita, MM, Lucchesi, F, de Oliveira, AT, Le, X, Paklina, O, Setdikova, G, Lee, J-H, Bennett, J, Iacocca, M, Huelsenbeck-Dill, L, Potapova, CO, Voronina, O, Liu, O, Fulidou, V, Cates, C, Sharp, A, Behera, M, Force, S, Khuri, F, Owonikoko, T, Pickens, A, Ramalingam, S, Sica, G, Dinjens, W, van Nistelrooij, A, Wijnhoven, B, Sandusky, G, Stepa, S, Juhl, IH, Zornig, C, Kwon, SY, Kelsen, D, Kim, GHK, Bartlett, J, Parfitt, J, Chetty, R, Darling, G, Knox, J, Wong, R, El-Zimaity, H, Liu, G, Boussioutas, A, Park, DY, Kemp, R, Carlotti, CG, da Cunha Tirapelli, DP, Saggioro, FP, Sankarankutty, AK, Noushmehr, H, dos Santos, JS, Trevisan, FA, Eschbacher, J, Dubina, M, Mozgovoy, E, Carey, F, Chalmers, S, Forgie, I, Godwin, A, Reilly, C, Madan, R, Naima, Z, Ferrer-Torres, D, Rathmell, WK, Dhir, R, Luketich, J, Ajani, JA, Janjigian, Y, Tang, L, Cheong, J-H, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Demchok, JA, Ferguson, ML, Shaw, KRM, sheth, M, Tarnuzzer, R, Wang, Z, Hutter, CM, Sofia, HJ, Kim, J, Bowlby, R, Mungall, AJ, Robertson, AG, Odze, RD, Cherniack, AD, Shih, J, Pedamallu, CS, Cibulskis, C, Dunford, A, Meier, SR, Raphael, BJ, Wu, H-T, Wong, AM, Willis, JE, Bass, AJ, Derks, S, Garman, K, McCall, SJ, Wiznerowicz, M, Pantazi, A, Parfenov, M, Thorsson, V, Shmulevich, I, Dhankani, V, Miller, M, Sakai, R, Wang, K, Schultz, N, Shen, R, Arora, A, Weinhold, N, Sanchez-Vega, F, Kelsen, DP, Zhang, J, Felau, I, Demchok, J, Rabkin, CS, Camargo, MC, Zenklusen, JC, Bowen, J, Leraas, K, Lichtenberg, TM, Curtis, C, Seoane, JA, Ojesina, AI, Beer, DG, Gulley, ML, Pennathur, A, Luketich, JD, Zhou, Z, Weisenberger, DJ, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Zhang, W, Reid, BJ, Hinoue, T, Laird, PW, Shen, H, Piazuelo, MB, Schneider, BG, McLellan, M, Taylor-Weiner, A, Lawrence, M, Cibulskis, K, Stewart, C, Getz, G, Lander, E, Gabriel, SB, Ding, L, McLellan, MD, Miller, CA, Appelbaum, EL, Cordes, MG, Fronick, CC, Fulton, LA, Mardis, ER, Wilson, RK, Schmidt, HK, Fulton, RS, Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Dhalla, N, Holt, RA, Jones, SJM, Kasaian, K, Brooks, D, Li, HI, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, KL, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Wong, T, Beroukhim, R, Bullman, S, Murray, BA, Saksena, G, Schumacher, SE, Gabriel, S, Meyerson, M, Hadjipanayis, A, Kucherlapati, R, Ren, X, Park, PJ, Lee, S, Kucherlapati, M, Yang, L, Baylin, SB, Hoadley, KA, Bootwalla, MS, Lai, PH, Van den Berg, DJ, Berrios, M, Holbrook, A, Hwang, J-E, Jang, H-J, Weinstein, JN, Lu, Y, Sohn, BH, Mills, G, Seth, S, Protopopov, A, Bristow, CA, Mahadeshwar, HS, Tang, J, Song, X, Cho, J, Defrietas, T, Frazer, S, Gehlenborg, N, Heiman, DI, Lawrence, MS, Lin, P, Noble, MS, Doug, V, Zhang, H, Polak, P, Chin, L, Bernard, B, Iype, L, Reynolds, SM, Abeshouse, A, Armenia, J, Kundra, R, Ladanyi, M, Kjong-Van, L, Gao, J, Sander, C, Chakravarty, D, Radenbaugh, A, Hegde, A, Penny, R, Crain, D, Gardner, J, Curley, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Frick, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Ramirez, NC, Wise, L, Zmuda, E, Tarvin, K, Saller, C, Park, YS, Button, M, Carvalho, AL, Reis, RM, Matsushita, MM, Lucchesi, F, de Oliveira, AT, Le, X, Paklina, O, Setdikova, G, Lee, J-H, Bennett, J, Iacocca, M, Huelsenbeck-Dill, L, Potapova, CO, Voronina, O, Liu, O, Fulidou, V, Cates, C, Sharp, A, Behera, M, Force, S, Khuri, F, Owonikoko, T, Pickens, A, Ramalingam, S, Sica, G, Dinjens, W, van Nistelrooij, A, Wijnhoven, B, Sandusky, G, Stepa, S, Juhl, IH, Zornig, C, Kwon, SY, Kelsen, D, Kim, GHK, Bartlett, J, Parfitt, J, Chetty, R, Darling, G, Knox, J, Wong, R, El-Zimaity, H, Liu, G, Boussioutas, A, Park, DY, Kemp, R, Carlotti, CG, da Cunha Tirapelli, DP, Saggioro, FP, Sankarankutty, AK, Noushmehr, H, dos Santos, JS, Trevisan, FA, Eschbacher, J, Dubina, M, Mozgovoy, E, Carey, F, Chalmers, S, Forgie, I, Godwin, A, Reilly, C, Madan, R, Naima, Z, Ferrer-Torres, D, Rathmell, WK, Dhir, R, Luketich, J, Ajani, JA, Janjigian, Y, Tang, L, Cheong, J-H, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Demchok, JA, Ferguson, ML, Shaw, KRM, sheth, M, Tarnuzzer, R, Wang, Z, Hutter, CM, and Sofia, HJ

Abstract

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.

Published
2017

4. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, AJ, Thorsson, V, Shmulevich, I, Reynolds, SM, Miller, M, Bernard, B, Hinoue, T, Laird, PW, Curtis, C, Shen, H, Weisenberger, DJ, Schultz, N, Shen, R, Weinhold, N, Keiser, DP, Bowlby, R, Sipahimalani, P, Cherniack, AD, Getz, G, Liu, Y, Noble, MS, Pedamallu, C, Sougnez, C, Taylor-Weiner, A, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Yang, D, Zhang, W, Pantazi, A, Parfenov, M, Gulley, M, Piazuelo, MB, Schneider, BG, Kim, J, Boussioutas, A, Sheth, M, Demchok, JA, Rabkin, CS, Willis, JE, Ng, S, Garman, K, Beer, DG, Pennathur, A, Raphael, BJ, Wu, H-T, Odze, R, Kim, HK, Bowen, J, Leraas, KM, Lichtenberg, TM, Weaver, L, McLellan, M, Wiznerowicz, M, Sakai, R, Lawrence, MS, Cibulskis, K, Lichtenstein, L, Fisher, S, Gabriel, SB, Lander, ES, Ding, L, Niu, B, Ally, A, Balasundaram, M, Birol, I, Brooks, D, Butterfield, YSN, Carlsen, R, Chu, A, Chu, J, Chuah, E, Chun, H-JE, Clarke, A, Dhalla, N, Guin, R, Holt, RA, Jones, SJM, Kasaian, K, Lee, D, Li, HA, Lim, E, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, KL, Nip, KM, Robertson, AG, Schein, JE, Tam, A, Thiessen, N, Beroukhim, R, Carter, SL, Cho, J, DiCara, D, Frazer, S, Gehlenborg, N, Heiman, DI, Jung, J, Lin, P, Meyerson, M, Ojesina, AI, Pedamallu, CS, Saksena, G, Schumacher, SE, Stojanov, P, Tabak, B, Voet, D, Rosenberg, M, Zack, TI, Zhang, H, Zou, L, Protopopov, A, Santoso, N, Lee, S, Zhang, J, Mahadeshwar, HS, Tang, J, Ren, X, Seth, S, Yang, L, Xu, AW, Song, X, Xi, R, Bristow, CA, Hadjipanayis, A, Seidman, J, Chin, L, Park, PJ, Kucherlapati, R, Ling, S, Rao, A, Weinstein, JN, Kim, S-B, Lu, Y, Mills, G, Bootwalla, MS, Lai, PH, Triche, T, Van Den Berg, DJ, Baylin, SB, Herman, JG, Murray, BA, Askoy, BA, Ciriello, G, Dresdner, G, Gao, J, Gross, B, Jacobsen, A, Lee, W, Ramirez, R, Sander, C, Senbabaoglu, Y, Sinha, R, Sumer, SO, Sun, Y, Iype, L, Kramer, RW, Kreisberg, R, Rovira, H, Tasman, N, Haussler, D, Stuart, JM, Verhaak, RGW, Leiserson, MDM, Taylor, BS, Black, AD, Carney, JA, Gastier-Foster, JM, Helsel, C, McAllister, C, Ramirez, NC, Tabler, TR, Wise, L, Zmuda, E, Penny, R, Crain, D, Gardner, J, Lau, K, Curely, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Sherman, M, Benz, C, Lee, J-H, Fedosenko, K, Manikhas, G, Voronina, O, Belyaev, D, Dolzhansky, O, Rathmell, WK, Brzezinski, J, Ibbs, M, Korski, K, Kycler, W, Lazniak, R, Leporowska, E, Mackiewicz, A, Murawa, D, Murawa, P, Spychala, A, Suchorska, WM, Tatka, H, Teresiak, M, Abdel-Misih, R, Bennett, J, Brown, J, Iacocca, M, Rabeno, B, Kwon, S-Y, Kemkes, A, Curley, E, Alexopoulou, I, Engel, J, Bartlett, J, Albert, M, Park, D-Y, Dhir, R, Luketich, J, Landreneau, R, Janjigian, YY, Kelsen, DP, Cho, E, Ladanyi, M, Tang, L, McCall, SJ, Park, YS, Cheong, J-H, Ajani, J, Camargo, MC, Alonso, S, Ayala, B, Jensen, MA, Pihl, T, Raman, R, Walton, J, Wan, Y, Eley, G, Shaw, KRM, Tarnuzzer, R, Wang, Z, Zenklusen, JC, Davidsen, T, Hutter, CM, Sofia, HJ, Burton, R, Chudamani, S, Liu, J, Bass, AJ, Thorsson, V, Shmulevich, I, Reynolds, SM, Miller, M, Bernard, B, Hinoue, T, Laird, PW, Curtis, C, Shen, H, Weisenberger, DJ, Schultz, N, Shen, R, Weinhold, N, Keiser, DP, Bowlby, R, Sipahimalani, P, Cherniack, AD, Getz, G, Liu, Y, Noble, MS, Pedamallu, C, Sougnez, C, Taylor-Weiner, A, Akbani, R, Lee, J-S, Liu, W, Mills, GB, Yang, D, Zhang, W, Pantazi, A, Parfenov, M, Gulley, M, Piazuelo, MB, Schneider, BG, Kim, J, Boussioutas, A, Sheth, M, Demchok, JA, Rabkin, CS, Willis, JE, Ng, S, Garman, K, Beer, DG, Pennathur, A, Raphael, BJ, Wu, H-T, Odze, R, Kim, HK, Bowen, J, Leraas, KM, Lichtenberg, TM, Weaver, L, McLellan, M, Wiznerowicz, M, Sakai, R, Lawrence, MS, Cibulskis, K, Lichtenstein, L, Fisher, S, Gabriel, SB, Lander, ES, Ding, L, Niu, B, Ally, A, Balasundaram, M, Birol, I, Brooks, D, Butterfield, YSN, Carlsen, R, Chu, A, Chu, J, Chuah, E, Chun, H-JE, Clarke, A, Dhalla, N, Guin, R, Holt, RA, Jones, SJM, Kasaian, K, Lee, D, Li, HA, Lim, E, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, KL, Nip, KM, Robertson, AG, Schein, JE, Tam, A, Thiessen, N, Beroukhim, R, Carter, SL, Cho, J, DiCara, D, Frazer, S, Gehlenborg, N, Heiman, DI, Jung, J, Lin, P, Meyerson, M, Ojesina, AI, Pedamallu, CS, Saksena, G, Schumacher, SE, Stojanov, P, Tabak, B, Voet, D, Rosenberg, M, Zack, TI, Zhang, H, Zou, L, Protopopov, A, Santoso, N, Lee, S, Zhang, J, Mahadeshwar, HS, Tang, J, Ren, X, Seth, S, Yang, L, Xu, AW, Song, X, Xi, R, Bristow, CA, Hadjipanayis, A, Seidman, J, Chin, L, Park, PJ, Kucherlapati, R, Ling, S, Rao, A, Weinstein, JN, Kim, S-B, Lu, Y, Mills, G, Bootwalla, MS, Lai, PH, Triche, T, Van Den Berg, DJ, Baylin, SB, Herman, JG, Murray, BA, Askoy, BA, Ciriello, G, Dresdner, G, Gao, J, Gross, B, Jacobsen, A, Lee, W, Ramirez, R, Sander, C, Senbabaoglu, Y, Sinha, R, Sumer, SO, Sun, Y, Iype, L, Kramer, RW, Kreisberg, R, Rovira, H, Tasman, N, Haussler, D, Stuart, JM, Verhaak, RGW, Leiserson, MDM, Taylor, BS, Black, AD, Carney, JA, Gastier-Foster, JM, Helsel, C, McAllister, C, Ramirez, NC, Tabler, TR, Wise, L, Zmuda, E, Penny, R, Crain, D, Gardner, J, Lau, K, Curely, E, Mallery, D, Morris, S, Paulauskis, J, Shelton, T, Shelton, C, Sherman, M, Benz, C, Lee, J-H, Fedosenko, K, Manikhas, G, Voronina, O, Belyaev, D, Dolzhansky, O, Rathmell, WK, Brzezinski, J, Ibbs, M, Korski, K, Kycler, W, Lazniak, R, Leporowska, E, Mackiewicz, A, Murawa, D, Murawa, P, Spychala, A, Suchorska, WM, Tatka, H, Teresiak, M, Abdel-Misih, R, Bennett, J, Brown, J, Iacocca, M, Rabeno, B, Kwon, S-Y, Kemkes, A, Curley, E, Alexopoulou, I, Engel, J, Bartlett, J, Albert, M, Park, D-Y, Dhir, R, Luketich, J, Landreneau, R, Janjigian, YY, Kelsen, DP, Cho, E, Ladanyi, M, Tang, L, McCall, SJ, Park, YS, Cheong, J-H, Ajani, J, Camargo, MC, Alonso, S, Ayala, B, Jensen, MA, Pihl, T, Raman, R, Walton, J, Wan, Y, Eley, G, Shaw, KRM, Tarnuzzer, R, Wang, Z, Zenklusen, JC, Davidsen, T, Hutter, CM, Sofia, HJ, Burton, R, Chudamani, S, and Liu, J

Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Published
2014

5. Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence.

Author

Koo SC, LaHaye S, Kovari BP, Schieffer KM, Ranalli MA, Aldrink JH, Michalsky MP, Colace S, Miller KE, Bedrosian TA, Leraas KM, Voytovich K, Wheeler G, Brennan P, Fitch J, Kelly BJ, McGrath SD, Miller AR, White P, Magrini V, Wilson RK, Mardis ER, Lauwers GY, Baker PB, and Cottrell CE

Subjects
Adolescent, Age of Onset, Carcinoma pathology, Humans, Male, Stomach Neoplasms pathology, Alcohol Oxidoreductases genetics, Carcinoma genetics, DNA-Binding Proteins genetics, Oncogene Proteins, Fusion genetics, RNA-Binding Protein EWS genetics, Stomach Neoplasms genetics
Abstract

Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma., (© 2021 Wiley Periodicals LLC.)

Published
2021
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6. Retrospective clinical trial experimentally validates glioblastoma genome-wide pattern of DNA copy-number alterations predictor of survival.

Author

Ponnapalli SP, Bradley MW, Devine K, Bowen J, Coppens SE, Leraas KM, Milash BA, Li F, Luo H, Qiu S, Wu K, Yang H, Wittwer CT, Palmer CA, Jensen RL, Gastier-Foster JM, Hanson HA, Barnholtz-Sloan JS, and Alter O

Abstract

Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects ≈ 11 % and profiling technology and reference human genome specifics affect <1% of the classifications of the tumors by the pattern, where experimental batch effects normally reduce the reproducibility, i.e., precision, of classifications based upon between one to a few hundred genomic loci by >30%. With a 2.25-year Kaplan-Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype-phenotype relationships., (© Author(s).)

Published
2020
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7. Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Author

Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, McCoy K, Haber M, Evans K, McCalmont H, Bendak K, Böhm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li XN, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA, and Maris JM

Subjects
Animals, Cell Line, Tumor, Central Nervous System Neoplasms metabolism, Child, Clinical Trials as Topic, Disease Models, Animal, Genomics, Humans, Mice, Mutation, Neuroblastoma genetics, Neuroblastoma metabolism, Neurofibromin 1 genetics, Neurofibromin 1 metabolism, Osteosarcoma genetics, Osteosarcoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Recurrence, Rhabdomyosarcoma genetics, Rhabdomyosarcoma metabolism, Sarcoma, Ewing genetics, Sarcoma, Ewing metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Exome Sequencing, Wilms Tumor genetics, Wilms Tumor metabolism, Central Nervous System Neoplasms genetics, Neurofibromin 1 antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Tumor Suppressor Protein p53 antagonists & inhibitors, Xenograft Model Antitumor Assays
Abstract

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2019
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8. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Author

Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, McConkey DJ, Weinstein JN, Kwiatkowski DJ, and Lerner SP

Published
2018
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9. Integrated Molecular Characterization of Testicular Germ Cell Tumors.

Author

Shen H, Shih J, Hollern DP, Wang L, Bowlby R, Tickoo SK, Thorsson V, Mungall AJ, Newton Y, Hegde AM, Armenia J, Sánchez-Vega F, Pluta J, Pyle LC, Mehra R, Reuter VE, Godoy G, Jones J, Shelley CS, Feldman DR, Vidal DO, Lessel D, Kulis T, Cárcano FM, Leraas KM, Lichtenberg TM, Brooks D, Cherniack AD, Cho J, Heiman DI, Kasaian K, Liu M, Noble MS, Xi L, Zhang H, Zhou W, ZenKlusen JC, Hutter CM, Felau I, Zhang J, Schultz N, Getz G, Meyerson M, Stuart JM, Akbani R, Wheeler DA, Laird PW, Nathanson KL, Cortessis VK, and Hoadley KA

Subjects
DNA Copy Number Variations, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Male, MicroRNAs metabolism, Neoplasms, Germ Cell and Embryonal classification, Neoplasms, Germ Cell and Embryonal metabolism, Proto-Oncogene Proteins c-kit genetics, Proto-Oncogene Proteins c-kit metabolism, Seminoma metabolism, Seminoma pathology, Testicular Neoplasms classification, Testicular Neoplasms metabolism, ras Proteins genetics, ras Proteins metabolism, Neoplasms, Germ Cell and Embryonal pathology, Testicular Neoplasms pathology
Abstract

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2018
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10. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Author

Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, McConkey DJ, Weinstein JN, Kwiatkowski DJ, and Lerner SP

Subjects
Aged, Cluster Analysis, DNA Methylation, Humans, MicroRNAs genetics, Middle Aged, Muscle, Smooth pathology, RNA, Long Noncoding genetics, Survival Analysis, Urinary Bladder pathology, Urinary Bladder Neoplasms epidemiology, Urinary Bladder Neoplasms therapy, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology
Abstract

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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11. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Author

Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, and Zuna R

Subjects
Carcinoma, Papillary genetics, CpG Islands physiology, DNA Methylation, Humans, Kidney Neoplasms genetics, MicroRNAs chemistry, NF-E2-Related Factor 2 genetics, Phenotype, Proto-Oncogene Proteins c-met chemistry, Proto-Oncogene Proteins c-met genetics, RNA, Messenger chemistry, RNA, Neoplasm chemistry, Sequence Analysis, RNA, Signal Transduction physiology, Carcinoma, Papillary metabolism, Kidney Neoplasms metabolism, Mutation, NF-E2-Related Factor 2 metabolism, Proto-Oncogene Proteins c-met metabolism
Abstract

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist., Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis., Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH)., Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Published
2016
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12. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Author

Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M, Morozova O, Robertson AG, Noushmehr H, Laird PW, Cherniack AD, Akbani R, Huse JT, Ciriello G, Poisson LM, Barnholtz-Sloan JS, Berger MS, Brennan C, Colen RR, Colman H, Flanders AE, Giannini C, Grifford M, Iavarone A, Jain R, Joseph I, Kim J, Kasaian K, Mikkelsen T, Murray BA, O'Neill BP, Pachter L, Parsons DW, Sougnez C, Sulman EP, Vandenberg SR, Van Meir EG, von Deimling A, Zhang H, Crain D, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton T, Sherman M, Yena P, Black A, Bowen J, Dicostanzo K, Gastier-Foster J, Leraas KM, Lichtenberg TM, Pierson CR, Ramirez NC, Taylor C, Weaver S, Wise L, Zmuda E, Davidsen T, Demchok JA, Eley G, Ferguson ML, Hutter CM, Mills Shaw KR, Ozenberger BA, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Ayala B, Baboud J, Chudamani S, Jensen MA, Liu J, Pihl T, Raman R, Wan Y, Wu Y, Ally A, Auman JT, Balasundaram M, Balu S, Baylin SB, Beroukhim R, Bootwalla MS, Bowlby R, Bristow CA, Brooks D, Butterfield Y, Carlsen R, Carter S, Chin L, Chu A, Chuah E, Cibulskis K, Clarke A, Coetzee SG, Dhalla N, Fennell T, Fisher S, Gabriel S, Getz G, Gibbs R, Guin R, Hadjipanayis A, Hayes DN, Hinoue T, Hoadley K, Holt RA, Hoyle AP, Jefferys SR, Jones S, Jones CD, Kucherlapati R, Lai PH, Lander E, Lee S, Lichtenstein L, Ma Y, Maglinte DT, Mahadeshwar HS, Marra MA, Mayo M, Meng S, Meyerson ML, Mieczkowski PA, Moore RA, Mose LE, Mungall AJ, Pantazi A, Parfenov M, Park PJ, Parker JS, Perou CM, Protopopov A, Ren X, Roach J, Sabedot TS, Schein J, Schumacher SE, Seidman JG, Seth S, Shen H, Simons JV, Sipahimalani P, Soloway MG, Song X, Sun H, Tabak B, Tam A, Tan D, Tang J, Thiessen N, Triche T Jr, Van Den Berg DJ, Veluvolu U, Waring S, Weisenberger DJ, Wilkerson MD, Wong T, Wu J, Xi L, Xu AW, Yang L, Zack TI, Zhang J, Aksoy BA, Arachchi H, Benz C, Bernard B, Carlin D, Cho J, DiCara D, Frazer S, Fuller GN, Gao J, Gehlenborg N, Haussler D, Heiman DI, Iype L, Jacobsen A, Ju Z, Katzman S, Kim H, Knijnenburg T, Kreisberg RB, Lawrence MS, Lee W, Leinonen K, Lin P, Ling S, Liu W, Liu Y, Liu Y, Lu Y, Mills G, Ng S, Noble MS, Paull E, Rao A, Reynolds S, Saksena G, Sanborn Z, Sander C, Schultz N, Senbabaoglu Y, Shen R, Shmulevich I, Sinha R, Stuart J, Sumer SO, Sun Y, Tasman N, Taylor BS, Voet D, Weinhold N, Weinstein JN, Yang D, Yoshihara K, Zheng S, Zhang W, Zou L, Abel T, Sadeghi S, Cohen ML, Eschbacher J, Hattab EM, Raghunathan A, Schniederjan MJ, Aziz D, Barnett G, Barrett W, Bigner DD, Boice L, Brewer C, Calatozzolo C, Campos B, Carlotti CG Jr, Chan TA, Cuppini L, Curley E, Cuzzubbo S, Devine K, DiMeco F, Duell R, Elder JB, Fehrenbach A, Finocchiaro G, Friedman W, Fulop J, Gardner J, Hermes B, Herold-Mende C, Jungk C, Kendler A, Lehman NL, Lipp E, Liu O, Mandt R, McGraw M, Mclendon R, McPherson C, Neder L, Nguyen P, Noss A, Nunziata R, Ostrom QT, Palmer C, Perin A, Pollo B, Potapov A, Potapova O, Rathmell WK, Rotin D, Scarpace L, Schilero C, Senecal K, Shimmel K, Shurkhay V, Sifri S, Singh R, Sloan AE, Smolenski K, Staugaitis SM, Steele R, Thorne L, Tirapelli DP, Unterberg A, Vallurupalli M, Wang Y, Warnick R, Williams F, Wolinsky Y, Bell S, Rosenberg M, Stewart C, Huang F, Grimsby JL, Radenbaugh AJ, and Zhang J

Subjects
Adolescent, Adult, Aged, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Cluster Analysis, Female, Glioblastoma genetics, Glioma metabolism, Glioma mortality, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Grading, Proportional Hazards Models, Sequence Analysis, DNA, Signal Transduction, DNA, Neoplasm analysis, Genes, p53, Glioma genetics, Mutation
Abstract

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas., Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes., Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma., Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Published
2015
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