Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Wu, Hsin-Ta; Fragoso, Maria Candida Barisson Villares; Habra, Mouhammed Amir; Zheng, Siyuan; Verhaak, Roel G.W.; Giordano, Thomas J.; Hammer, Gary D.; Cherniack, Andrew D.; Dewal, Ninad; Moffitt, Richard A.; Danilova, Ludmila; Murray, Bradley A.; Lerário, Antônio Marcondes; Else, Tobias; Knijnenburg, Theo; Ciriello, Giovanni; S, Kim; Assié, Guillaume; Morozova, Olena; Akbani, Rehan; Shih, Juliann; Hoadley, Katherine A.; Choueiri, Toni K.; Waldmann, Jens; Mete, Özgür; Robertson, A. Gordon; Wu, Hsin-Tu; Raphael, Benjamin J.; Meyerson, Matthew; Demeure, Michael J.; Beuschlein, Felix; Gill, Anthony J.; Sidhu, Stan; Almeida, Madson Q.; Fragoso, Maria Candida Barisson Villares; Cope, Leslie; Kebebew, Electron; Habra, Mouhammed Amir; Whitsett, Timothy G.; Bussey, Kimberly J.; Rainey, William E.; Sylvia, L.; Bertherat, Jérôme; Faßnacht, Martin; Wheeler, David A.; Benz, Christopher C.; Ally, Adrian; Balasundaram, Miruna; Bowlby, Reanne; Brooks, Denise; Butterfield, Yaron S.N.; Carlsen, Rebecca; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Jones, Steven J.M.; Kasaian, Katayoon; Lee, Darlene; Li, Haiyan I.; Lim, Lynette; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen; Sadeghi, Sara; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Park, Peter J.; Kroiß, Matthias; Gao, Jianjiong; Sander, Chris; Schultz, Nikolaus; Jones, Corbin D.; Kucherlapati, Raju; Mieczkowski, Piotr A.; Parker, Joel S.; Perou, Charles M.; Tan, Donghui; Veluvolu, Umadevi; Wilkerson, Matthew D.; Hayes, D. Neil; Ladanyi, Marc; Quinkler, Marcus; Auman, J. Todd; Latrônico, Ana Claudia; Mendonça, Berenice Bilharinho; Sibony, Mathilde; Sanborn, Zack; Bellair, Michelle; Buhay, Christian; Covington, Kyle R.; Dahdouli, Mahmoud; Dinh, Huyen; Doddapaneni, Harshavardhan; Downs, Brittany; Drummond, Jennifer; Gibbs, Richard C.; Hale, Walker; Han, Yi; Hawes, Alicia; Hu, Jianhong; Kakkar, Nipun; Kalra, Dipak; Khan, Ziad U.; Kovar, Christine; Lee, Sandy; Lewis, Lora; Morgan, Margaret; Morton, Donna; Muzny, Donna M.; Santibanez, Jireh; Liu, Xi; Dousset, B.; Groussin, Lionel; Libé, Rossella; Chin, Lynda; Reynolds, Sheila M.; Shmulevich, Ilya; Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Wu, Ye; Yeh, Jen Jen; Balu, Saianand; Bodenheimer, Tom; Hoyle, Alan P.; Jefferys, Stuart R.; Meng, Shaowu; Mose, Lisle E.; Shi, Yan; Simons, Janae V.; Soloway, Matthew G.; Wu, Junyuan; Wei, Zhang; Shaw, Kenna; Demchok, John A.; Felau, Ina; Sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan; Davidsen, Tanja M.; Crawford, Catherine; Hutter, Carolyn M.; Sofia, Heidi J.; Roach, Jeffrey; Bshara, Wiam; Gaudioso, Carmelo; Morrison, Carl; Soon, Patsy S.; Alonso, Shelley; Baboud, Julien; Pihl, Todd; Raman, Rohini; Sun, Qiang; Wan, Yunhu; Naresh, Rashi; Arachchi, Harindra; Beroukhim, Rameen; Carter, Scott L.; Cho, Juok; Frazer, Scott; Gabriel, Stacey; Getz, Gad; Heiman, David I.; Kim, Jaegil; Lawrence, Michael S.; Lin, Pei Jung; Noble, Michael S.; Saksena, Gordon; Schumacher, Steven E.; Sougnez, Carrie; Voet, Doug; Zhang, Hailei; Bowen, Jay; Coppens, Sara; Gastier‐Foster, Julie M.; Gerken, Mark; Helsel, Carmen; Leraas, Kristen; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Baylin, Stephen; Herman, James G.; LoBello, Janine; Watanabe, Aprill; Haussler, David; Radenbaugh, Amie; Rao, Arjun A.; Zhu, Jingchun; Bartsch, Detlef K.; Sbiera, Silviu; Allolio, Bruno; Deutschbein, Timo; Rabascio, Cristina; Raymond, Victoria M.; Vinco, Michelle; Shao, Lina; Amble, Linda; Bootwalla, Moiz S.; Lai, Phillip H.; Berg, David J. Van Den; Weisenberger, Daniel J.; Robinson, Bruce; Zhang, Ju; Kim, Hoon; Ling, Shiyun; Liu, Wenbin; Lu, Yiling; Mills, Gordon B.; Sircar, Kanishka; Wang, Qianghu; Yoshihara, Kosuke; Laird, Peter W.; Fan, Yu; Wang, Wenyi; Shinbrot, Eve; Reincke, Martín; Weinstein, John N.; Meier, Sam; DeFreitas, Timothy

doi:10.1016/j.ccell.2016.07.013

Cited by 107 publications

(60 citation statements)

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“…Kaplan-Meier survival curves of the TCGA-KIRC cohort patients stratified based on the WGD status of primary tumors showed a statistically significant inferior survival with WGD (+) ccRCC patients (P < 0.0001) ( Figure 6C and Supplemental Table 7). Notably, WGD also negatively impacts the survival of colorectal and adrenocortical cancer patients (37,38). Here we demonstrated the shared transcription signature and inferior survival between ICD (+) chRCC and WGD (+) ccRCC, implicating ICD as a WGD variant.…”

Section: Wgd (+) Ccrcc Patients In the Tcga-kirc Cohort Exhibit Infermentioning

confidence: 61%

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Casuscelli¹,

Weinhold²,

Gundem³

et al. 2017

JCI Insight

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Section: Wgd (+) Ccrcc Patients In the Tcga-kirc Cohort Exhibit Infermentioning

confidence: 61%

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Casuscelli¹,

Weinhold²,

Gundem³

et al. 2017

JCI Insight

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“…However, with a Weiss score of 1 the patient's adenoma had no characteristics of malignancy. The Cancer Genome Atlas reveals alteration of PRKACB in various cancer (26) but not in adrenocortical carcinoma (27). Figure 5.…”

Section: (± 02)mentioning

confidence: 99%

Activating PRKACB somatic mutation in cortisol-producing adenomas

Espiard¹,

Knape²,

Bathon³

et al. 2018

JCI Insight

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“…Clinical trials of molecularly targeted agents have not demonstrated therapeutic benefit for ACC patients (see Creemers et al, 2016). The differences in the genetic and epigenetic changes among different ACC tumours suggest that different molecular mechanisms underlie the malignancy of different ACC tumours (Assie et al, 2014;Zheng et al, 2016). Adrenalytic compounds can potentially be used for the treatment of ACCs that have different determinants of malignancy.…”

mentioning

confidence: 99%

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

Burns

Kerppola

2017

British J Pharmacology

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BACKGROUND AND PURPOSETo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301-02). EXPERIMENTAL APPROACHWe compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-β-cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds. KEY RESULTSATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-β-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation. CONCLUSIONS AND IMPLICATIONSInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC. IntroductionControl of the levels of cholesterol (The term "cholesterol" is used to denote unesterified cholesterol in this paper) is essential for cell functions and viability (see Maxfield and Van Meer, 2010). The cholesterol levels in adrenocortical cells are affected by many pathways, some of which are unique to the adrenal cortex. Studies of anti-atherosclerosis agents have identified compounds that cause selective degeneration of the adrenal cortex (adrenalytic activity) in several species (Dominick et al., 1993;Reindel et al., 1994;Matsuo et al., 1996;Sliskovic et al., 1998;Tanaka et al., 1998). Here we have investigated the adrenalytic compound ATR-101, also known as PD132301-02, as a prospective agent for the treatment of adrenocortical carcinoma (ACC). We focused on ATR-101 because of its cytotoxicity in ACC-derived cells and its antixenograft and adrenalytic activities (Cheng et al., 2016). ACC is a rare cancer that has few treatment options. The adrenalytic compound mitotane is a first-line drug for ACC treatment despite its poor efficacy, unfavourable pharmacokinetics, severe side effects and potential drug interactions (Maiter et al., 2016). Clinical trials of molecularly targeted agents...

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Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Cited by 107 publications

References 0 publications

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Activating PRKACB somatic mutation in cortisol-producing adenomas

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

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