Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Science Translational Medicine

Volumn 9, Issue 379, 2017, Pages

  Roh, Whijae ^a,b   Chen, Pei Ling ^a   Reuben, Alexandre ^a   Spencer, Christine N ^a   Prieto, Peter A ^a   Miller, John P ^a   Gopalakrishnan, Vancheswaran ^a   Wang, Feng ^a   Cooper, Zachary A ^a   Reddy, Sangeetha M ^a   Gumbs, Curtis ^a   Little, Latasha ^a   Chang, Qing ^a   Chen, Wei Shen ^a   Wani, Khalida ^a   De Macedo, Mariana Petaccia ^a,c   Chen, Eveline ^a   Austin Breneman, Jacob L ^a   Jiang, Hong ^a   Roszik, Jason ^a   Tetzlaff, Michael T ^a   Davies, Michael A ^a   Gershenwald, Jeffrey E ^a   Tawbi, Hussein ^a   Lazar, Alexander J ^a   Hwu, Patrick ^a   Hwu, Wen Jen ^a   Diab, Adi ^a   Glitza, Isabella C ^a   Patel, Sapna P ^a   Woodman, Scott E ^a   Amaria, Rodabe N ^a   Prieto, Victor G ^a   Hu, Jianhua ^a   Sharma, Padmanee ^a   Allison, James P ^a   Chin, Lynda ^d   Zhang, Jianhua ^a   Wargo, Jennifer A ^a   Futreal, P Andrew ^a   more..

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c A C CAMARGO CANCER CENTER   (Brazil)

^d UNIVERSITY OF TEXAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

B LYMPHOCYTE INDUCED MATURATION PROTEIN 1; BONE MORPHOGENETIC PROTEIN RECEPTOR 1A; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; FAS ANTIGEN; PEMBROLIZUMAB; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROGRAMMED DEATH 1 RECEPTOR; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FKHRL1; TUMOR MARKER; TUMOR NECROSIS FACTOR ALPHA INDUCED PROTEIN 3;

ARTICLE; CANCER INHIBITION; CANCER PATIENT; CLONAL VARIATION; COHORT ANALYSIS; CONTROLLED STUDY; COPY NUMBER VARIATION; GENE EXPRESSION; GENE LOSS; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC CORRELATION; HUMAN; HUMAN TISSUE; IMMUNE RESPONSE; MAJOR CLINICAL STUDY; MELANOMA; METASTATIC MELANOMA; MISSENSE MUTATION; MUTATIONAL LOAD; NONSENSE MUTATION; PREDICTIVE VALUE; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TREATMENT RESPONSE; TUMOR BIOPSY; TUMOR RESISTANCE; WHOLE EXOME SEQUENCING; ANTAGONISTS AND INHIBITORS; BIOPSY; CELL CLONE; DRUG RESISTANCE; GENE DOSAGE; GENETICS; GENOME; IMMUNOLOGY; METABOLISM; MUTATION; NEOPLASM; PATHOLOGY;

BIOMARKERS, TUMOR; BIOPSY; CLONE CELLS; COHORT STUDIES; CTLA-4 ANTIGEN; DNA COPY NUMBER VARIATIONS; DRUG RESISTANCE, NEOPLASM; GENE DOSAGE; GENOME; HUMANS; MUTATION; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR; T-LYMPHOCYTES;

EID: 85014681380     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aah3560     Document Type: Article

References (71)

1. D. Schadendorf, F. S. Hodi, C. Robert, J. S. Weber, K. Margolin, O. Hamid, D. Patt, T.-T. Chen, D. M. Berman, J. D. Wolchok, Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889-1894 (2015).
2. S. L. Topalian, F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012).
3. J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, C. L. Cowey, C. D. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P. F. Ferrucci, A. Hill, J. Wagstaff, M. S. Carlino, J. B. Haanen, M. Maio, I. Marquez-Rodas, G. A. McArthur, P. A. Ascierto, G. V. Long, M. K. Callahan, M. A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L. M. Rollin, C. Horak, F. S. Hodi, J. D. Wolchok, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23-34 (2015).
4. J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R.-A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta, M. Sznol, Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122-133 (2013).
5. A. Snyder, V. Makarov, T. Merghoub, J. Yuan, J. M. Zaretsky, A. Desrichard, L. A. Walsh, M. A. Postow, P. Wong, T. S. Ho, T. J. Hollmann, C. Bruggeman, K. Kannan, Y. Li, C. Elipenahli, C. Liu, C. T. Harbison, L. Wang, A. Ribas, J. D. Wolchok, T. A. Chan, Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189-2199 (2014).
6. N. A. Rizvi, M. D. Hellmann, A. Snyder, P. Kvistborg, V. Makarov, J. J. Havel, W. Lee, J. Yuan, P. Wong, T. S. Ho, Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015).
7. E. M. Van Allen, D. Miao, B. Schilling, S. A. Shukla, C. Blank, L. Zimmer, A. Sucker, U. Hillen, M. H. G. Foppen, S. M. Goldinger, J. Utikal, J. C. Hassel, B. Weide, K. C. Kaehler, C. Loquai, P. Mohr, R. Gutzmer, R. Dummer, S. Gabriel, C. J. Wu, D. Schadendorf, L. A. Garraway, Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207-211 (2015).
8. D. T. Le, J. N. Uram, H. Wang, B. R. Bartlett, H. Kemberling, A. D. Eyring, A. D. Skora, B. S. Luber, N. S. Azad, D. Laheru, B. Biedrzycki, R. C. Donehower, A. Zaheer, G. A. Fisher, T. S. Crocenzi, J. J. Lee, S. M. Duffy, R. M. Goldberg, A. de la Chapelle, M. Koshiji, F. Bhaijee, T. Huebner, R. H. Hruban, L. D. Wood, N. Cuka, D. M. Pardoll, N. Papadopoulos, K. W. Kinzler, S. Zhou, T. C. Cornish, J. M. Taube, R. A. Anders, J. R. Eshleman, B. Vogelstein, L. A. Diaz Jr., PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509-2520 (2015).
9. O. Hamid, C. Robert, A. Daud, F. S. Hodi, W.-J. Hwu, R. Kefford, J. D. Wolchok, P. Hersey, R. W. Joseph, J. S. Weber, R. Dronca, T. C. Gangadhar, A. Patnaik, H. Zarour, A. M. Joshua, K. Gergich, J. Elassaiss-Schaap, A. Algazi, C. Mateus, P. Boasberg, P. C. Tumeh, B. Chmielowski, S. W. Ebbinghaus, X. N. Li, S. P. Kang, A. Ribas, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134-144 (2013).
10. P. C. Tumeh, C. L. Harview, J. H. Yearley, I. P. Shintaku, E. J. M. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A. N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A. J. Gutierrez, T. R. Grogan, C. Mateus, G. Tomasic, J. A. Glaspy, R. O. Emerson, H. Robins, R. H. Pierce, D. A. Elashoff, C. Robert, A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568-571 (2014).
11. M. S. Rooney, S. A. Shukla, C. J. Wu, G. Getz, N. Hacohen, Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48-61 (2015).
12. M. Angelova, P. Charoentong, H. Hackl, M. L. Fischer, R. Snajder, A. M. Krogsdam, M. J. Waldner, G. Bindea, B. Mlecnik, J. Galon, Z. Trajanoski, Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).
13. T. N. Schumacher, C. Kesmir, M. M. van. Buuren, Biomarkers in cancer immunotherapy. Cancer Cell 27, 12-14 (2015).
14. + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. U.S.A. 107, 7875-7880 (2010).
15. K. Sakuishi, L. Apetoh, J. M. Sullivan, B. R. Blazar, V. K. Kuchroo, A. C. Anderson, Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187-2194 (2010).
16. H. Li, K. Wu, K. Tao, L. Chen, Q. Zheng, X. Lu, J. Liu, L. Shi, C. Liu, G. Wang, W. Zou, Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342-1351 (2012).
17. S.-R. Woo, M. E. Turnis, M. V. Goldberg, J. Bankoti, M. Selby, C. J. Nirschl, M. L. Bettini, D. M. Gravano, P. Vogel, C. L. Liu, S. Tangsombatvisit, J. F. Grosso, G. Netto, M. P. Smeltzer, A. Chaux, P. J. Utz, C. J. Workman, D. M. Pardoll, A. J. Korman, C. G. Drake, D. A. A. Vignali, Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917-927 (2012).
18. T. Powles, J. P. Eder, G. D. Fine, F. S. Braiteh, Y. Loriot, C. Cruz, J. Bellmunt, H. A. Burris, D. P. Petrylak, S.-l. Teng, X. Shen, Z. Boyd, P. S. Hegde, D. S. Chen, N. J. Vogelzang, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558-562 (2014).
19. R. S. Herbst, J.-C. Soria, M. Kowanetz, G. D. Fine, O. Hamid, M. S. Gordon, J. A. Sosman, D. F. McDermott, J. D. Powderly, S. N. Gettinger, H. E. K. Kohrt, L. Horn, D. P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P. S. Hegde, I. Mellman, D. S. Chen, F. S. Hodi, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563-567 (2014).
20. + T cell effector function. Cancer Cell 26, 923-937 (2014).
21. + T cells in melanoma patients. J. Clin. Invest. 125, 2046-2058 (2015).
22. H. Sumimoto, F. Imabayashi, T. Iwata, Y. Kawakami, The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 203, 1651-1656 (2006).
23. S. Spranger, R. Bao, T. F. Gajewski, Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231-235 (2015).
24. W. Peng, J. Q. Chen, C. Liu, S. Malu, C. Creasy, M. T. Tetzlaff, C. Xu, J. A. McKenzie, C. Zhang, X. Liang, L. J. Williams, W. Deng, G. Chen, R. Mbofung, A. J. Lazar, C. A. Torres-Cabala, Z. A. Cooper, P.-L. Chen, T. N. Tieu, S. Spranger, X. Yu, C. Bernatchez, M.-A. Forget, C. Haymaker, R. Amaria, J. L. McQuade, I. C. Glitza, T. Cascone, H. S. Li, L. N. Kwong, T. P. Heffernan, J. Hu, R. L. Bassett Jr., M. W. Bosenberg, S. E. Woodman, W. W. Overwijk, G. Lizée, J. Roszik, T. F. Gajewski, J. A. Wargo, J. E. Gershenwald, L. Radvanyi, M. A. Davies, P. Hwu, Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202-216 (2016).
25. W. Hugo, J. M. Zaretsky, L. Sun, C. Song, B. H. Moreno, S. Hu-Lieskovan, B. Berent-Maoz, J. Pang, B. Chmielowski, G. Cherry, E. Seja, S. Lomeli, X. Kong, M. C. Kelley, J. A. Sosman, D. B. Johnson, A. Ribas, R. S. Lo, Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35-44 (2016).
26. J. M. Taube, R. A. Anders, G. D. Young, H. Xu, R. Sharma, T. L. McMiller, S. Chen, A. P. Klein, D. M. Pardoll, S. L. Topalian, L. Chen, Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra137 (2012).
27. J. M. Taube, G. D. Young, T. L. McMiller, S. Chen, J. T. Salas, T. S. Pritchard, H. Xu, A. K. Meeker, J. Fan, C. Cheadle, A. E. Berger, D. M. Pardoll, S. L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: Implications for PD-1 pathway blockade. Clin. Cancer Res. 21, 3969-3976 (2015).
28. M. D. Ayers, M. Nebozhyn, H. A. Hirsch, R. Cristescu, E. E. Murphy, S. P. Kang, S. W. Ebbinghaus, T. K. McClanahan, A. Loboda, J. K. Lunceford, Assessment of gene expression in peripheral blood from patients with advanced melanoma using RNA-seq before and after treatment with anti-PD-1 therapy with pembrolizumab (MK-3475). Cancer Res. 75, 1307 (2015).
29. A. J. Minn, E. J. Wherry, Combination cancer therapies with immune checkpoint blockade: Convergence on interferon signaling. Cell 165, 272-275 (2016).
30. J. M. Zaretsky, A. Garcia-Diaz, D. S. Shin, H. Escuin-Ordinas, W. Hugo, S. Hu-Lieskovan, D. Y. Torrejon, G. Abril-Rodriguez, S. Sandoval, L. Barthly, J. Saco, B. Homet Moreno, R. Mezzadra, B. Chmielowski, K. Ruchalski, I. P. Shintaku, P. J. Sanchez, C. Puig-Saus, G. Cherry, E. Seja, X. Kong, J. Pang, B. Berent-Maoz, B. Comin-Anduix, T. G. Graeber, P. C. Tumeh, T. N. Schumacher, R. S. Lo, A. Ribas, Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819-829 (2016).
31. H. Matsushita, M. D. Vesely, D. C. Koboldt, C. G. Rickert, R. Uppaluri, V. J. Magrini, C. D. Arthur, J. M. White, Y.-S. Chen, L. K. Shea, J. Hundal, M. C. Wendl, R. Demeter, T. Wylie, J. P. Allison, M. J. Smyth, L. J. Old, E. R. Mardis, R. D. Schreiber, Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400-404 (2012).
32. M. DuPage, C. Mazumdar, L. M. Schmidt, A. F. Cheung, T. Jacks, Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405-409 (2012).
33. A. Sivan, L. Corrales, N. Hubert, J. B. Williams, K. Aquino-Michaels, Z. M. Earley, F. W. Benyamin, Y. M. Lei, B. Jabri, M.-L. Alegre, E. B. Chang, T. F. Gajewski, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084-1089 (2015).
34. M. Vétizou, J. M. Pitt, R. Daillère, P. Lepage, N. Waldschmitt, C. Flament, S. Rusakiewicz, B. Routy, M. P. Roberti, C. P. M. Duong, V. Poirier-Colame, A. Roux, S. Becharef, S. Formenti, E. Golden, S. Cording, G. Eberl, A. Schlitzer, F. Ginhoux, S. Mani, T. Yamazaki, N. Jacquelot, D. P. Enot, M. Bérard, J. Nigou, P. Opolon, A. Eggermont, P.-L. Woerther, E. Chachaty, N. Chaput, C. Robert, C. Mateus, G. Kroemer, D. Raoult, I. Gomperts Boneca, F. Carbonnel, M. Chamaillard, L. Zitvogel, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079-1084 (2015).
35. C.-H. Chang, J. Qiu, D. O'Sullivan, M. D. Buck, T. Noguchi, J. D. Curtis, Q. Chen, M. Gindin, M. M. Gubin, G. J. W. van der Windt, E. Tonc, R. D. Schreiber, E. J. Pearce, E. L. Pearce, Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229-1241 (2015).
36. P.-C. Ho, J. D. Bihuniak, A. N. Macintyre, M. Staron, X. Liu, R. Amezquita, Y.-C. Tsui, G. Cui, G. Micevic, J. C. Perales, S. H. Kleinstein, E. D. Abel, K. L. Insogna, S. Feske, J. W. Locasale, M. W. Bosenberg, J. C. Rathmell, S. M. Kaech, Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor t cell responses. Cell 162, 1217-1228 (2015).
37. + T cells by modulating cholesterol metabolism. Nature 531, 651-655 (2016).
38. P.-L. Chen, W. Roh, A. Reuben, Z. A. Cooper, C. N. Spencer, P. A. Prieto, J. P. Miller, R. L. Bassett, V. Gopalakrishnan, K. Wani, M. P. De Macedo, J. L. Austin-Breneman, H. Jiang, Q. Chang, S. M. Reddy, W.-S. Chen, M. T. Tetzlaff, R. J. Broaddus, M. A. Davies, J. E. Gershenwald, L. Haydu, A. J. Lazar, S. P. Patel, P. Hwu, W.-J. Hwu, A. Diab, I. C. Glitza, S. E. Woodman, L. M. Vence, I. I. Wistuba, R. N. Amaria, L. N. Kwong, V. Prieto, R. E. Davis, W. Ma, W. W. Overwijk, A. H. Sharpe, J. Hu, P. A. Futreal, J. Blando, P. Sharma, J. P. Allison, L. Chin, J. A. Wargo, Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade Cancer Discov. 6, 827-837 (2016).
39. E. Hodis, I. R. Watson, G. V. Kryukov, S. T. Arold, M. Imielinski, J.-P. Theurillat, E. Nickerson, D. Auclair, L. Li, C. Place, D. Dicara, A. H. Ramos, M. S. Lawrence, K. Cibulskis, A. Sivachenko, D. Voet, G. Saksena, N. Stransky, R. C. Onofrio, W. Winckler, K. Ardlie, N. Wagle, J. Wargo, K. Chong, D. L. Morton, K. Stemke-Hale, G. Chen, M. Noble, M. Meyerson, J. E. Ladbury, M. A. Davies, J. E. Gershenwald, S. N. Wagner, D. S. B. Hoon, D. Schadendorf, E. S. Lander, S. B. Gabriel, G. Getz, L. A. Garraway, L. Chin, A landscape of driver mutations in melanoma. Cell 150, 251-263 (2012).
40. Cancer Genome Atlas Network, Genomic classification of cutaneous melanoma. Cell 161, 1681-1696 (2015).
41. D. H. Kaplan, V. Shankaran, A. S. Dighe, E. Stockert, M. Aguet, L. J. Old, R. D. Schreiber, Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice. Proc. Natl. Acad. Sci. U.S.A. 95, 7556-7561 (1998).
42. G. P. Dunn, K. C. F. Sheehan, L. J. Old, R. D. Schreiber, IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res. 65, 3447-3453 (2005).
43. J. Gao, L. Z. Shi, H. Zhao, J. Chen, L. Xiong, Q. He, T. Chen, J. Roszik, C. Bernatchez, S. E. Woodman, P.-L. Chen, P. Hwu, J. P. Allison, A. Futreal, J. A. Wargo, P. Sharma, Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397-404.e9 (2016).
44. S. A. Shukla, M. S. Rooney, M. Rajasagi, G. Tiao, P. M. Dixon, M. S. Lawrence, J. Stevens, W. J. Lane, J. L. Dellagatta, S. Steelman, C. Sougnez, K. Cibulskis, A. Kiezun, N. Hacohen, V. Brusic, C. J. Wu, G. Getz, Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat. Biotechnol. 33, 1152-1158 (2015).
45. E. Wang, A. Worschech, F. M. Marincola, The immunologic constant of rejection. Trends Immunol. 29, 256-262 (2008).
46. J. Galon, H. K. Angell, D. Bedognetti, F. M. Marincola, The continuum of cancer immunosurveillance: Prognostic, predictive, and mechanistic signatures. Immunity 39, 11-26 (2013).
47. L. N. Kwong, L. Chin, Chromosome 10, frequently lost in human melanoma, encodes multiple tumor-suppressive functions. Cancer Res. 74, 1814-1821 (2014).
48. K. Yoshihara, M. Shahmoradgoli, E. Martínez, R. Vegesna, H. Kim, W. Torres-Garcia, V. Treviño, H. Shen, P. W. Laird, D. A. Levine, S. L. Carter, G. Getz, K. Stemke-Hale, G. B. Mills, R. G. W. Verhaak, Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013).
49. V. K. Mootha, C. M. Lindgren, K.-F. Eriksson, A. Subramanian, S. Sihag, J. Lehar, P. Puigserver, E. Carlsson, M. Ridderstråle, E. Laurila, N. Houstis, M. J. Daly, N. Patterson, J. P. Mesirov, T. R. Golub, P. Tamayo, B. Spiegelman, E. S. Lander, J. N. Hirschhorn, D. Altshuler, L. C. Groop, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267-273 (2003).
50. B. C. Bastian, P. E. LeBoit, H. Hamm, E.-B. Bröcker, D. Pinkel, Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res. 58, 2170-2175 (1998).
51. J. Bauer, B. C. Bastian, Distinguishing melanocytic nevi from melanoma by DNA copy number changes: Comparative genomic hybridization as a research and diagnostic tool. Dermatol. Ther. 19, 40-49 (2006).
52. A. H. Shain, I. Yeh, I. Kovalyshyn, A. Sriharan, E. Talevich, A. Gagnon, R. Dummer, J. North, L. Pincus, B. Ruben, W. Rickaby, C. D'Arrigo, A. Robson, B. C. Bastian, The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926-1936 (2015).
53. A.H. Shain, B. C Bastian, From melanocytes to melanomas. Nat. Rev. Cancer 16, 345-358 (2016).
54. H. Li, R. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754-1760 (2009).
55. A. McKenna, M. Hanna, E. Banks, A. Sivachenko, K. Cibulskis, A. Kernytsky, K. Garimella, D. Altshuler, S. Gabriel, M. Daly, M. A. DePristo, The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297-1303 (2010).
56. M. A. DePristo, E. Banks, R. Poplin, K. V. Garimella, J. R. Maguire, C. Hartl, A. A. Philippakis, G. del Angel, M. A. Rivas, M. Hanna, A. McKenna, T. J. Fennell, A. M. Kernytsky, A. Y. Sivachenko, K. Cibulskis, S. B. Gabriel, D. Altshuler, M. J. Daly, A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491-498 (2011).
57. G. A. Van der Auwera, M. O. Carneiro, C. Hartl, R. Poplin, G. del Angel, A. Levy-Moonshine, T. Jordan, K. Shakir, D. Roazen, J. Thibault, E. Banks, K. V. Garimella, D. Altshuler, S. Gabriel, M. A. DePristo, From FastQ data to high-confidence variant calls: The genome analysis toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 11.10.1-11.10.33 (2013).
58. K. Cibulskis, M. S. Lawrence, S. L. Carter, A. Sivachenko, D. Jaffe, C. Sougnez, S. Gabriel, M. Meyerson, E. S. Lander, G. Getz, Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213-219 (2013).
59. K. Ye, M. H. Schulz, Q. Long, R. Apweiler, Z. Ning, Pindel: A pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865-2871 (2009).
60. N. Andor, J. V. Harness, S. Müller, H. W. Mewes, C. Petritsch, EXPANDS: Expanding ploidy and allele frequency on nested subpopulations. Bioinformatics 30, 50-60 (2014).
61. C. A. Miller, B. S. White, N. D. Dees, M. Griffith, J. S. Welch, O. L. Griffith, R. Vij, M. H. Tomasson, T. A. Graubert, M. J. Walter, M. J. Ellis, W. Schierding, J. F. DiPersio, T. J. Ley, E. R. Mardis, R. K. Wilson, L. Ding, SciClone: Inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLOS Comput. Biol. 10, e1003665 (2014).
62. A. Snyder, T. A. Chan, Immunogenic peptide discovery in cancer genomes. Curr. Opin. Genet. Dev. 30, 7-16 (2015).
63. C. Liu, X. Yang, B. Duffy, T. Mohanakumar, R. D. Mitra, M. C. Zody, J. D. Pfeifer, ATHLATES: Accurate typing of human leukocyte antigen through exome sequencing. Nucleic Acids Res. 41, e142 (2013).
64. I. Hoof, B. Peters, J. Sidney, L. E. Pedersen, A. Sette, O. Lund, S. Buus, M. Nielsen, NetMHCpan, a method for MHC class I binding prediction beyond humans. Immunogenetics 61, 1-13 (2009).
65. F. Favero, T. Joshi, A. M. Marquard, N. J. Birkbak, M. Krzystanek, Q. Li, Z. Szallasi, A. C. Eklund, Sequenza: Allele-specific copy number and mutation profiles from tumor sequencing data. Ann. Oncol. 26, 64-70 (2015).
66. J. Zhang, "CNTools: Convert segment data into a region by sample matrix to allow for other high level computational analyses. R package version 1.6. 0" (2014); https://rdrr.io/bioc/CNTools/.
67. J. Zhang, B. Feng, "biocViews microarray. Package 'cghMCR'" (2013); www.bioconductor.org/packages/release/bioc/html/cghMCR.html.
68. S. A. Forbes, D. Beare, P. Gunasekaran, K. Leung, N. Bindal, H. Boutselakis, M. Ding, S. Bamford, C. Cole, S. Ward, C. Y. Kok, M. Jia, T. De, J. W. Teague, M. R. Stratton, U. McDermott, P. J. Campbell, COSMIC: Exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 43, D805-D811 (2015).
69. M. Zhao, J. Sun, Z. Zhao, TSGene: A web resource for tumor suppressor genes. Nucleic Acids Res. 41, D970-D976 (2013).
70. H. S. Robins, P. V. Campregher, S. K. Srivastava, A. Wacher, C. J. Turtle, O. Kahsai, S. R. Riddell, E. H. Warren, C. S. Carlson, Comprehensive assessment of T-cell receptor β-chain diversity in ab T cells. Blood 114, 4099-4107 (2009).
71. C. S. Carlson, R. O. Emerson, A. M. Sherwood, C. Desmarais, M.-W. Chung, J. M. Parsons, M. S. Steen, M. A. LaMadrid-Herrmannsfeldt, D. W. Williamson, R. J. Livingston, D. Wu, B. L. Wood, M. J. Rieder, H. Robins, Using synthetic templates to design an unbiased multiplex PCR assay. Nat. Commun. 4, 2680 (2013).