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1. FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.

Author

Chakraborty, Nishma, Matulionis, Nedas, Hernandez, Stephanie, Ueno, Daiki, Gee, Michayla, Esplin, Edward, Ouyang, Karen, Nykamp, Keith, Shuch, Brian, Christofk, Heather, and Wilde, Blake

Subjects
Humans, Fumarate Hydratase, Virulence, Carcinoma, Renal Cell, Kidney Neoplasms, Skin Neoplasms, Purines
Abstract

UNLABELLED: Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. SIGNIFICANCE: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.

Published
2023

4. Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions

Author

Purdue, Mark P., Dutta, Diptavo, Machiela, Mitchell J., Gorman, Bryan R., Winter, Timothy, Okuhara, Dayne, Cleland, Sara, Ferreiro-Iglesias, Aida, Scheet, Paul, Liu, Aoxing, Wu, Chao, Antwi, Samuel O., Larkin, James, Zequi, Stênio C., Sun, Maxine, Hikino, Keiko, Hajiran, Ali, Lawson, Keith A., Cárcano, Flavio, Blanchet, Odile, Shuch, Brian, Nepple, Kenneth G., Margue, Gaëlle, Sundi, Debasish, Diver, W. Ryan, Folgueira, Maria A. A. K., van Bokhoven, Adrie, Neffa, Florencia, Brown, Kevin M., Hofmann, Jonathan N., Rhee, Jongeun, Yeager, Meredith, Cole, Nathan R., Hicks, Belynda D., Manning, Michelle R., Hutchinson, Amy A., Rothman, Nathaniel, Huang, Wen-Yi, Linehan, W. Marston, Lori, Adriana, Ferragu, Matthieu, Zidane-Marinnes, Merzouka, Serrano, Sérgio V., Magnabosco, Wesley J., Vilas, Ana, Decia, Ricardo, Carusso, Florencia, Graham, Laura S., Anderson, Kyra, Bilen, Mehmet A., Arciero, Cletus, Pellegrin, Isabelle, Ricard, Solène, Scelo, Ghislaine, Banks, Rosamonde E., Vasudev, Naveen S., Soomro, Naeem, Stewart, Grant D., Adeyoju, Adebanji, Bromage, Stephen, Hrouda, David, Gibbons, Norma, Patel, Poulam, Sullivan, Mark, Protheroe, Andrew, Nugent, Francesca I., Fournier, Michelle J., Zhang, Xiaoyu, Martin, Lisa J., Komisarenko, Maria, Eisen, Timothy, Cunningham, Sonia A., Connolly, Denise C., Uzzo, Robert G., Zaridze, David, Mukeria, Anush, Holcatova, Ivana, Hornakova, Anna, Foretova, Lenka, Janout, Vladimir, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Gaborieau, Valérie, Abedi-Ardekani, Behnoush, McKay, James, Johansson, Mattias, Phouthavongsy, Larry, Hayman, Lindsay, Li, Jason, Lungu, Ilinca, Bezerra, Stephania M., Souza, Aline G., Sares, Claudia T. G., Reis, Rodolfo B., Gallucci, Fabio P., Cordeiro, Mauricio D., Pomerantz, Mark, Lee, Gwo-Shu M., Freedman, Matthew L., Jeong, Anhyo, Greenberg, Samantha E., Sanchez, Alejandro, Thompson, R. Houston, Sharma, Vidit, Thiel, David D., Ball, Colleen T., Abreu, Diego, Lam, Elaine T., Nahas, William C., Master, Viraj A., Patel, Alpa V., Bernhard, Jean-Christophe, Freedman, Neal D., Bigot, Pierre, Reis, Rui M., Colli, Leandro M., Finelli, Antonio, Manley, Brandon J., Terao, Chikashi, Choueiri, Toni K., Carraro, Dirce M., Houlston, Richard, Eckel-Passow, Jeanette E., Abbosh, Philip H., Ganna, Andrea, Brennan, Paul, Gu, Jian, and Chanock, Stephen J.

Published
2024
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5. Transcriptomic recurrence score improves recurrence prediction for surgically treated patients with intermediate-risk clear cell kidney cancer.

Author

Patel, Neal, Hakansson, Alexander, Ohtake, Shinji, Muraki, Peter, Proudfout, James, Liu, Yang, Webber, Lisa, Ibarra, Arkaitz, Liu, Vinnie, Davicioni, Elai, Chamie, Karim, Pantuck, Allan, and Shuch, Brian

Subjects
adjuvant therapy, kidney cancer, transcriptomics, Humans, Carcinoma, Renal Cell, Transcriptome, Neoplasm Staging, Kidney Neoplasms, Risk Factors, Nephrectomy, Neoplasm Recurrence, Local, Prognosis
Abstract

BACKGROUND: Risk stratification of kidney cancer patients after nephrectomy may tailor surveillance intensity and selection for adjuvant therapy. Transcriptomic approaches are effective in predicting recurrence, but whether they add value to clinicopathologic models remains unclear. METHODS: Data from patients with clear cell renal cell carcinoma (ccRCC) was downloaded from The Cancer Genome Atlas. Clinicopathologic variables were used to calculate SSIGN (stage, size, grade, and necrosis) scores. The 16 gene recurrence score (RS) signature was generated using RNA-seq data. Transcriptomic risk groups were calculated using the original thresholds. SSIGN groups were divided into low, intermediate, and high risk. Disease-free status was the primary endpoint assessed. RESULTS: SSIGN and RS were calculated for 428 patients with non-metastatic ccRCC. SSIGN low-, intermediate-, and high-risk groups demonstrated 2.7%, 15.2%, and 27.5%, 3-year recurrence risk, respectively. On multivariable analysis, the RS was associated with disease-free status (sub-distribution hazard ratio (sHR) 1.43 per 25 RS [95% CI (1.00-1.43)], p = 0.05). By risk groups, RS further risk stratified the SSIGN intermediate-risk group (sHR 2.22 [95% CI 1.10-4.50], p = 0.03). SSIGN intermediate-risk patients with low and high RS had a 3-year recurrence rate of 8.0% and 25.2%, respectively. Within this risk group, the area under the curve (AUC) at 3 years was 0.69 for SSIGN, 0.74 for RS, and 0.78 for their combination. CONCLUSIONS: Transcriptomic recurrence scores improve risk prediction even when controlling for clinicopathologic factors. Utility may be best suited for intermediate-risk patients who have heterogeneous outcomes and further refinement for clinical utility is warranted.

Published
2023

6. Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy

Author

Ueno, Daiki, Vasquez, Juan C, Sule, Amrita, Liang, Jiayu, van Doorn, Jinny, Sundaram, Ranjini, Friedman, Sam, Caliliw, Randy, Ohtake, Shinji, Bao, Xun, Li, Jing, Ye, Huihui, Boyd, Karla, Huang, Rong Rong, Dodson, Jack, Boutros, Paul, Bindra, Ranjit S, and Shuch, Brian

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Kidney Disease, Clinical Research, Cancer, Genetics, Rare Diseases, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Adenosine Diphosphate Ribose, Animals, Carcinoma, Renal Cell, Citric Acid Cycle, DNA, Dioxygenases, Fumarate Hydratase, Fumarates, Humans, Jumonji Domain-Containing Histone Demethylases, Kidney Neoplasms, Lysine, Mice, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Succinate Dehydrogenase, Succinates, Temozolomide, FH, PARP inhibitor, SDHB, renal cell carcinoma, temozolomide, Oncology and carcinogenesis
Abstract

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.

Published
2022

7. [89Zr]Zr-girentuximab for PET–CT imaging of clear-cell renal cell carcinoma: a prospective, open-label, multicentre, phase 3 trial

Author

Shuch, Brian, Pantuck, Allan J, Bernhard, Jean-Christophe, Morris, Michael A, Master, Viraj, Scott, Andrew M, van Praet, Charles, Bailly, Clement, Önal, Bülent, Aksoy, Tamer, Merkx, Robin, Schuster, David M, Lee, Sze Ting, Pandit-Taskar, Neeta, Fan, Alice C, Allman, Phillip, Schmidt, Karl, Tauchmanova, Libuse, Wheatcroft, Michael, Behrenbruch, Christian, Hayward, Colin R W, and Mulders, Peter

Published
2024
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8. Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma

Author

Purdue, Mark P., Dutta, Diptavo, Machiela, Mitchell J., Gorman, Bryan R., Winter, Timothy, Okuhara, Dayne, Cleland, Sara, Ferreiro-Iglesias, Aida, Scheet, Paul, Liu, Aoxing, Wu, Chao, Antwi, Samuel O., Larkin, James, Zequi, Stênio C., Sun, Maxine, Hikino, Keiko, Hajiran, Ali, Lawson, Keith A., Cárcano, Flavio, Blanchet, Odile, Shuch, Brian, Nepple, Kenneth G., Margue, Gaëlle, Sundi, Debasish, Diver, W. Ryan, Folgueira, Maria A.A.K., van Bokhoven, Adrie, Neffa, Florencia, Brown, Kevin M., Hofmann, Jonathan N., Rhee, Jongeun, Yeager, Meredith, Cole, Nathan R., Hicks, Belynda D., Manning, Michelle R., Hutchinson, Amy A., Rothman, Nathaniel, Huang, Wen-Yi, Linehan, W. Marston, Lori, Adriana, Ferragu, Matthieu, Zidane-Marinnes, Merzouka, Serrano, Sérgio, Magnabosco, Wesley J., BioBank Japan Project Consortium, Vilas, Ana, Decia, Ricardo, Carusso, Florencia, Graham, Laura S., Anderson, Kyra, Bilen, Mehmet A., Arciero, Cletus, Pellegrin, Isabelle, Ricard, Solène, FinnGen, Scelo, Ghislaine, Banks, Rosamonde E., Vasudev, Naveen S., Soomro, Naeem, Stewart, Grant D., Adeyoju, Adebanji, Bromage, Stephen, Hrouda, David, Gibbons, Norma, Patel, Poulam, Sullivan, Mark, Protheroe, Andrew, Nugent, Francesca I., Fournier, Michelle J., Zhang, Xiaoyu, Martin, Lisa J., Komisarenko, Maria, Eisen, Timothy, Cunningham, Sonia A., Connolly, Denise C., Uzzo, Robert G., Zaridze, David, Mukeria, Anush, Holcatova, Ivana, Hornakova, Anna, Foretova, Lenka, Janout, Vladimir, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Gaborieau, Valérie, Abedi-Ardekani, Behnoush, McKay, James, Johansson, Mattias, Phouthavongsy, Larry, Hayman, Lindsay, Li, Jason, Lungu, Ilinca, Bezerra, Stephania M., de Souza, Aline G., Sares, Claudia T.G., Reis, Rodolfo B., Gallucci, Fabio P., Cordeiro, Mauricio D., Pomerantz, Mark, Lee, Gwo-Shu M., Freedman, Matthew L., Jeong, Anhyo, Greenberg, Samantha E., Sanchez, Alejandro, Thompson, R. Houston, Sharma, Vidit, Thiel, David D., Ball, Colleen T., Abreu, Diego, Lam, Elaine T., Nahas, William C., Master, Viraj A., Patel, Alpa V., Bernhard, Jean-Christophe, Freedman, Neal D., Bigot, Pierre, Reis, Rui M., Colli, Leandro M., Finelli, Antonio, Manley, Brandon J., Terao, Chikashi, Choueiri, Toni K., Carraro, Dirce M., Houlston, Richard, Eckel-Passow, Jeanette E., Abbosh, Philip H., Ganna, Andrea, Brennan, Paul, Gu, Jian, Chanock, Stephen J., Guo, Xinyu, Winter, Timothy D., Jahagirdar, Om, Ha, Eunji, and Susztak, Katalin

Published
2024
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10. Adjuvant Everolimus in Patients with Completely Resected, Very High-risk Renal Cell Carcinoma of Clear Cell Histology: Results from the Phase 3 Placebo-controlled SWOG S0931 (EVEREST) Trial

Author

Lara, Primo N., Jr, Tangen, Catherine, Heath, Elisabeth I., Gulati, Shuchi, Stein, Mark N., Meng, Maxwell, Alva, Ajjai Shivaram, Pal, Sumanta K., Puzanov, Igor, Clark, Joseph I., Choueiri, Toni K., Agarwal, Neeraj, Uzzo, Robert, Haas, Naomi B., Synold, Timothy W., Plets, Melissa, Vaishampayan, Ulka N., Shuch, Brian M., Lerner, Seth, Thompson, Ian M., Jr, and Ryan, Christopher W.

Published
2024
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12. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study

Author

Allaf, Mohamad E, Kim, Se-Eun, Master, Viraj, McDermott, David F, Harshman, Lauren C, Cole, Suzanne M, Drake, Charles G, Signoretti, Sabina, Akgul, Mahmut, Baniak, Nicholas, Li-Ning, Elsa, Palmer, Matthew B, Emamekhoo, Hamid, Adra, Nabil, Kaimakliotis, Hristos, Ged, Yasser, Pierorazio, Phillip M, Abel, E Jason, Bilen, Mehmet A, Ogan, Kenneth, Moon, Helen H, Ramaswamy, Krishna A, Singer, Eric A, Mayer, Tina M, Lohrey, Jay, Margulis, Vitaly, Gills, Jessie, Delacroix, Scott E, Waples, Mark J, James, Andrew C, Wang, Peng, Choueiri, Toni, Michaelson, M Dror, Kapoor, Anil, Heng, Daniel Y, Shuch, Brian, Leibovich, Bradley C, Lara, Primo N, Manola, Judith, Maskens, Deborah, Battle, Dena, Uzzo, Robert, Bratslavsky, Gennady, Haas, Naomi B, and Carducci, Michael A

Published
2024
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13. Summary of Research: Adjuvant Nivolumab Plus Ipilimumab Versus Placebo for Localized Renal Cell Carcinoma After Nephrectomy (CheckMate 914): A Double-Blind, Randomized, Phase 3 Trial

Author

Motzer, Robert J., Russo, Paul, Grünwald, Viktor, Tomita, Yoshihiko, Zurawski, Bogdan, Parikh, Omi, Buti, Sebastiano, Barthélémy, Philippe, Goh, Jeffrey C., Ye, Dingwei, Lingua, Alejo, Lattouf, Jean-Baptiste, Albigès, Laurence, George, Saby, Shuch, Brian, Sosman, Jeffrey, Staehler, Michael, Vázquez Estévez, Sergio, Simsek, Burcin, Spiridigliozzi, Julia, Chudnovsky, Aleksander, and Bex, Axel

Published
2023
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15. Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing

Author

Lu, Eric, Hatchell, Kathryn E, Nielsen, Sarah M, Esplin, Edward D, Ouyang, Karen, Nykamp, Keith, Zavoshi, Shirin, Li, Shantao, Zhang, Liying, Wilde, Blake R, Christofk, Heather R, Boutros, Paul C, and Shuch, Brian

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Kidney Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Renal Cell, Female, Fumarate Hydratase, Germ Cells, Germ-Line Mutation, Humans, Kidney Neoplasms, Leiomyomatosis, Neoplastic Syndromes, Hereditary, Prevalence, Skin Neoplasms, Uterine Neoplasms, fumarate hydratase, genetic testing, hereditary leiomyomatosis and renal cell cancer, kidney neoplasms, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract

BackgroundGermline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear.MethodsA database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.ResultsFH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P

Published
2022

19. Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial

Author

Ryan, Christopher W, Tangen, Catherine M, Heath, Elisabeth I, Stein, Mark N, Meng, Maxwell V, Alva, Ajjai S, Pal, Sumanta K, Puzanov, Igor, Clark, Joseph I, Choueiri, Toni K, Agarwal, Neeraj, Uzzo, Robert G, Haas, Naomi B, Synold, Timothy W, Plets, Melissa, Vaishampayan, Ulka N, Shuch, Brian M, Thompson, Ian M, Jr, and Lara, Primo N, Jr

Published
2023
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20. Distinguishing Benign Renal Tumors with an Oncocytic Gene Expression (ONEX) Classifier

Author

McGillivray, Patrick D, Ueno, Daiki, Pooli, Aydin, Mendhiratta, Neil, Syed, Jamil S, Nguyen, Kevin A, Schulam, Peter G, Humphrey, Peter A, Adeniran, Adebowale J, Boutros, Paul C, and Shuch, Brian

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Kidney Disease, Clinical Research, Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Renal and urogenital, Adenoma, Oxyphilic, Carcinoma, Renal Cell, Diagnosis, Differential, Gene Expression, Humans, Kidney Neoplasms, Molecular biomarkers, Renal oncocytoma, Chromophobe renal cell carcinoma, RNA expression, Tumor classification, Urology & Nephrology, Clinical sciences
Abstract

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. PATIENT SUMMARY: Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.

Published
2021

24. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial

Author

Motzer, Robert J, Russo, Paul, Grünwald, Viktor, Tomita, Yoshihiko, Zurawski, Bogdan, Parikh, Omi, Buti, Sebastiano, Barthélémy, Philippe, Goh, Jeffrey C, Ye, Dingwei, Lingua, Alejo, Lattouf, Jean-Baptiste, Albigès, Laurence, George, Saby, Shuch, Brian, Sosman, Jeffrey, Staehler, Michael, Vázquez Estévez, Sergio, Simsek, Burcin, Spiridigliozzi, Julia, Chudnovsky, Aleksander, and Bex, Axel

Published
2023
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26. Epidemiology of Renal Cell Carcinoma: 2022 Update

Author

Bukavina, Laura, Bensalah, Karim, Bray, Freddie, Carlo, Maria, Challacombe, Ben, Karam, Jose A., Kassouf, Wassim, Mitchell, Thomas, Montironi, Rodolfo, O'Brien, Tim, Panebianco, Valeria, Scelo, Ghislaine, Shuch, Brian, van Poppel, Hein, Blosser, Christopher D., and Psutka, Sarah P.

Published
2022
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27. Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

Author

Jikuya, Ryosuke, Murakami, Koichi, Nishiyama, Akira, Kato, Ikuma, Furuya, Mitsuko, Nakabayashi, Jun, Ramilowski, Jordan A., Hamanoue, Haruka, Maejima, Kazuhiro, Fujita, Masashi, Mitome, Taku, Ohtake, Shinji, Noguchi, Go, Kawaura, Sachi, Odaka, Hisakazu, Kawahara, Takashi, Komeya, Mitsuru, Shinoki, Risa, Ueno, Daiki, Ito, Hiroki, Ito, Yusuke, Muraoka, Kentaro, Hayashi, Narihiko, Kondo, Keiichi, Nakaigawa, Noboru, Hatano, Koji, Baba, Masaya, Suda, Toshio, Kodama, Tatsuhiko, Fujii, Satoshi, Makiyama, Kazuhide, Yao, Masahiro, Shuch, Brian M., Schmidt, Laura S., Linehan, W. Marston, Nakagawa, Hidewaki, Tamura, Tomohiko, and Hasumi, Hisashi

Published
2022
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28. Final Overall Survival Analysis of S1500: A Randomized, Phase II Study Comparing Sunitinib With Cabozantinib, Crizotinib, and Savolitinib in Advanced Papillary Renal Cell Carcinoma.

Author

Barata, Pedro, Tangen, Catherine, Plets, Melissa, Thompson Jr, Ian M., Narayan, Vivek, George, Daniel J., Heng, Daniel Y.C., Shuch, Brian, Stein, Mark, Gulati, Shuchi, Tretiakova, Maria, Tripathi, Abhishek, Bjarnason, Georg A., Humphrey, Peter, Adeniran, Adebowale, Vaishampayan, Ulka, Alva, Ajjai, Zhang, Tian, Cole, Scott, and Lara Jr, Primo N.

Published
2024
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29. Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

Author

Tripathi, Abhishek, Tangen, Catherine M., Plets, Melissa, Li, Xiaochen, Tretiakova, Maria, Humphrey, Peter A., Adeniran, Adebowale, Barata, Pedro C., Gulati, Shuchi, Bergerot, Cristiane D., Pruthi, Deepak K., Thompson, Ian M., Lara, Primo N., Lerner, Seth P., Pal, Sumanta K., and Shuch, Brian M.

Subjects
SUNITINIB, CONFIDENCE intervals, PATHOLOGISTS, CRIZOTINIB, WORLD health
Abstract

Objective: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. Methods: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression‐free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. Results: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. Conclusions: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. Patient summary: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Renal Mass Biopsy

Author

Padia, Siddharth A., Nguyen, Kevin A., Shuch, Brian, Rastinehad, Ardeshir R., editor, Siegel, David N., editor, Wood, Bradford J., editor, and McClure, Timothy, editor

Published
2021
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31. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Author

Ricketts, Christopher J, De Cubas, Aguirre A, Fan, Huihui, Smith, Christof C, Lang, Martin, Reznik, Ed, Bowlby, Reanne, Gibb, Ewan A, Akbani, Rehan, Beroukhim, Rameen, Bottaro, Donald P, Choueiri, Toni K, Gibbs, Richard A, Godwin, Andrew K, Haake, Scott, Hakimi, A Ari, Henske, Elizabeth P, Hsieh, James J, Ho, Thai H, Kanchi, Rupa S, Krishnan, Bhavani, Kwiatkowski, David J, Lui, Wembin, Merino, Maria J, Mills, Gordon B, Myers, Jerome, Nickerson, Michael L, Reuter, Victor E, Schmidt, Laura S, Shelley, C Simon, Shen, Hui, Shuch, Brian, Signoretti, Sabina, Srinivasan, Ramaprasad, Tamboli, Pheroze, Thomas, George, Vincent, Benjamin G, Vocke, Cathy D, Wheeler, David A, Yang, Lixing, Kim, William Y, Robertson, A Gordon, Spellman, Paul, Rathmell, W Kimryn, Linehan, W Marston, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Broom, Bradley M, Hegde, Apurva M, Ju, Zhenlin, Korkut, Anil, Li, Jun, Liang, Han, and Ling, Shiyun

Subjects
Biological Sciences, Cancer Genome Atlas Research Network, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

(Cell Reports 23, 313–326; April 3, 2018) In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online. The authors regret this error.

Published
2018

32. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Author

Giri, Veda N, Knudsen, Karen E, Kelly, William K, Abida, Wassim, Andriole, Gerald L, Bangma, Chris H, Bekelman, Justin E, Benson, Mitchell C, Blanco, Amie, Burnett, Arthur, Catalona, William J, Cooney, Kathleen A, Cooperberg, Matthew, Crawford, David E, Den, Robert B, Dicker, Adam P, Eggener, Scott, Fleshner, Neil, Freedman, Matthew L, Hamdy, Freddie C, Hoffman-Censits, Jean, Hurwitz, Mark D, Hyatt, Colette, Isaacs, William B, Kane, Christopher J, Kantoff, Philip, Karnes, R Jeffrey, Karsh, Lawrence I, Klein, Eric A, Lin, Daniel W, Loughlin, Kevin R, Lu-Yao, Grace, Malkowicz, S Bruce, Mann, Mark J, Mark, James R, McCue, Peter A, Miner, Martin M, Morgan, Todd, Moul, Judd W, Myers, Ronald E, Nielsen, Sarah M, Obeid, Elias, Pavlovich, Christian P, Peiper, Stephen C, Penson, David F, Petrylak, Daniel, Pettaway, Curtis A, Pilarski, Robert, Pinto, Peter A, Poage, Wendy, Raj, Ganesh V, Rebbeck, Timothy R, Robson, Mark E, Rosenberg, Matt T, Sandler, Howard, Sartor, Oliver, Schaeffer, Edward, Schwartz, Gordon F, Shahin, Mark S, Shore, Neal D, Shuch, Brian, Soule, Howard R, Tomlins, Scott A, Trabulsi, Edouard J, Uzzo, Robert, Vander Griend, Donald J, Walsh, Patrick C, Weil, Carol J, Wender, Richard, and Gomella, Leonard G

Subjects
Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Prognosis, Risk Factors, Predictive Value of Tests, Pedigree, Age Factors, Heredity, Phenotype, Adult, Aged, Middle Aged, Male, Genetic Testing, Biomarkers, Tumor, Clinical Decision-Making, Genetics, Aging, Cancer, Prevention, Prostate Cancer, Urologic Diseases, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Published
2018

33. MP58-01 A RANDOMIZED CONTROLLED TRIAL OF A FERMENTED SOY BEVERAGE AMONG PATIENTS WITH LOCALIZED PROSTATE CANCER PRIOR TO RADICAL PROSTATECTOMY

Author

Lokeshwar, Soum D., primary, Choksi, Ankur U., additional, Ali, Ather, additional, Weiss, Theresa, additional, Reynolds, Jesse, additional, Shuch, Brian M., additional, Ferencz, Thomas, additional, Kyriakides, Tassos C., additional, Brito, Joseph, additional, Renzulli, Joseph, additional, and Leapman, Michael S., additional

Published
2024
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34. INITIAL FINDINGS FROM THE MULTI-INSTITUTIONAL SARCOMATOID RENAL CELL CARCINOMA CONSORTIUM (SaRCC)

Author

Blum, Kyle A., primary, Mehr, Justin P., additional, Matin, Surena, additional, Karam, Jose A., additional, Pooli, Aydin, additional, Lebacle, Cedric, additional, Pantuck, Allan J., additional, Shuch, Brian, additional, Thompson, R. Houston, additional, Leibovich, Bradley, additional, Shah, Paras, additional, Hakimi, A. Ari, additional, and Russo, Paul, additional

Published
2024
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35. SWOG S1931 (PROBE): PHASE III RANDOMIZED TRIAL OF IMMUNE CHECKPOINT INHIBITOR (ICI) COMBINATION REGIMEN WITH OR WITHOUT CYTOREDUCTIVE NEPHRECTOMY (CN) IN ADVANCED RENAL CANCER [NCT04510597]

Author

Kim, Hyung, primary, Tangen, Catherine M., additional, Vaishampayan, Ulka, additional, Tripathi, Abhishek, additional, Patel, Sumanta K., additional, Shuch, Brian, additional, Barata, Pedro, additional, Tan, Alan, additional, Esfeller, Laura, additional, Lara, Primo N., additional, Sanchez, Alejandro, additional, Lerner, Seth P., additional, and Thompson, Ian M., additional

Published
2024
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41. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Author

Bi, Mark, Zhao, Siming, Said, Jonathan W, Merino, Maria J, Adeniran, Adebowale J, Xie, Zuoquan, Nawaf, Cayce B, Choi, Jaehyuk, Belldegrun, Arie S, Pantuck, Allan J, Kluger, Harriet M, Bilgüvar, Kaya, Lifton, Richard P, and Shuch, Brian

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Rare Diseases, Biotechnology, Cancer, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Aged, Carcinoma, Renal Cell, Cell Dedifferentiation, DNA Mismatch Repair, DNA-Binding Proteins, Exome, Female, Genes, p53, Humans, Kidney Neoplasms, Loss of Heterozygosity, Male, Middle Aged, Mutation, Nuclear Proteins, Oncogenes, Polymorphism, Single Nucleotide, Prognosis, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, kidney cancer, sarcomatoid, transformation, p53, dedifferentiation
Abstract

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Published
2016

42. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

Author

Linehan, W Marston, Spellman, Paul T, Ricketts, Christopher J, Creighton, Chad J, Fei, Suzanne S, Davis, Caleb, Wheeler, David A, Murray, Bradley A, Schmidt, Laura, Vocke, Cathy D, Peto, Myron, Al Mamun, Abu Amar M, Shinbrot, Eve, Sethi, Anurag, Brooks, Samira, Rathmell, W Kimryn, Brooks, Angela N, Hoadley, Katherine A, Robertson, A Gordon, Brooks, Denise, Bowlby, Reanne, Sadeghi, Sara, Shen, Hui, Weisenberger, Daniel J, Bootwalla, Moiz, Baylin, Stephen B, Laird, Peter W, Cherniack, Andrew D, Saksena, Gordon, Haake, Scott, Li, Jun, Liang, Han, Lu, Yiling, Mills, Gordon B, Akbani, Rehan, Leiserson, Mark DM, Raphael, Benjamin J, Anur, Pavana, Bottaro, Donald, Albiges, Laurence, Barnabas, Nandita, Choueiri, Toni K, Czerniak, Bogdan, Godwin, Andrew K, Hakimi, A Ari, Ho, Thai H, Hsieh, James, Ittmann, Michael, Kim, William Y, Krishnan, Bhavani, Merino, Maria J, Mills Shaw, Kenna R, Reuter, Victor E, Reznik, Ed, Shelley, Carl S, Shuch, Brian, Signoretti, Sabina, Srinivasan, Ramaprasad, Tamboli, Pheroze, Thomas, George, Tickoo, Satish, Burnett, Kenneth, Crain, Daniel, Gardner, Johanna, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph D, Penny, Robert J, Shelton, Candace, Shelton, W Troy, Sherman, Mark, Thompson, Eric, Yena, Peggy, Avedon, Melissa T, Bowen, Jay, Gastier-Foster, Julie M, Gerken, Mark, Leraas, Kristen M, Lichtenberg, Tara M, Ramirez, Nilsa C, Santos, Tracie, Wise, Lisa, Zmuda, Erik, Demchok, John A, Felau, Ina, Hutter, Carolyn M, Sheth, Margi, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Ayala, Brenda, Baboud, Julien, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, and Naresh, Rashi

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Biotechnology, Digestive Diseases, Kidney Disease, Good Health and Well Being, Carcinoma, Papillary, CpG Islands, DNA Methylation, Humans, Kidney Neoplasms, MicroRNAs, Mutation, NF-E2-Related Factor 2, Phenotype, Proto-Oncogene Proteins c-met, RNA, Messenger, RNA, Neoplasm, Sequence Analysis, RNA, Signal Transduction, Cancer Genome Atlas Research Network, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundPapillary 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.MethodsWe 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.ResultsType 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).ConclusionsType 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

48. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author

Davis, Caleb F, Ricketts, Christopher J, Wang, Min, Yang, Lixing, Cherniack, Andrew D, Shen, Hui, Buhay, Christian, Kang, Hyojin, Kim, Sang Cheol, Fahey, Catherine C, Hacker, Kathryn E, Bhanot, Gyan, Gordenin, Dmitry A, Chu, Andy, Gunaratne, Preethi H, Biehl, Michael, Seth, Sahil, Kaipparettu, Benny A, Bristow, Christopher A, Donehower, Lawrence A, Wallen, Eric M, Smith, Angela B, Tickoo, Satish K, Tamboli, Pheroze, Reuter, Victor, Schmidt, Laura S, Hsieh, James J, Choueiri, Toni K, Hakimi, A Ari, Network, The Cancer Genome Atlas Research, Creighton, Chad J, Morgan, Margaret, Wheeler, David A, Gibbs, Richard A, Signoretti, Sabina, Robertson, A Gordon, Henske, Elizabeth P, Kwiatkowski, David J, Ricketts, Christopher, Linehan, W Marston, Seiler, Michael, Rathmell, W Kimryn, Laird, Peter W, Shuch, Brian, Muzny, Donna, Chao, Hsu, Dahdouli, Mike, Xi, Liu, Kakkar, Nipun, Reid, Jeffrey G, Downs, Brittany, Drummond, Jennifer, Morton, Donna, Doddapaneni, Harsha, Lewis, Lora, English, Adam, Meng, Qingchang, Kovar, Christie, Wang, Qiaoyan, Hale, Walker, Hawes, Alicia, Kalra, Divya, Walker, Kimberly, Murray, Bradley A, Sougnez, Carrie, Saksena, Gordon, Carter, Scott L, Schumacher, Steven E, Tabak, Barbara, Zack, Travis I, Getz, Gad, Beroukhim, Rameen, Gabriel, Stacey B, Meyerson, Matthew, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, and Brooks, Denise

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Biotechnology, Rare Diseases, Kidney Disease, Cancer, Cancer Genomics, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Base Sequence, Carcinoma, Renal Cell, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, DNA Copy Number Variations, DNA Methylation, DNA Mutational Analysis, DNA, Mitochondrial, Exome, Genome, Human, Humans, Kidney Neoplasms, Molecular Sequence Data, Promoter Regions, Genetic, Telomerase, Transcriptome, The Cancer Genome Atlas Research Network, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.

Published
2014

49. CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma.

Author

Rong Rong Huang, Zhengshan Chen, Kroeger, Nils, Pantuck, Allan, Said, Jonathan, Kluger, Harriet M., Shuch, Brian, and Huihui Ye

Subjects
RENAL cell carcinoma, CD antigens, METASTASIS, GENE expression, IMMUNOHISTOCHEMISTRY
Abstract

As a therapeutic target overexpressed in clear cell renal cell carcinoma (CCRCC), whether CD70 remains overexpressed in metastatic foci is not well established. We assessed CD70 immunohistochemistry in 391 primary and 72 metastatic renal tumors on a tissue microarray including 26 pairs of primary and metastatic CCRCC. CD70 expression, correlated with hypoxia pathway proteins, showed a concordance rate of 85% between primary tumors and matched metastases. Our findings validated CD70 as a promising therapeutic target for patients with metastatic CCRCC. Background: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established. Materials and Methods: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors. Results: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%. Conclusion: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials. [ABSTRACT FROM AUTHOR]

Published
2024
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