Review
Oncology
Yanfei Yu, Mengmeng Zheng, Zhu Weijie, Fuqiang Zhao, Bao Guan, Qi Shen, Feng Yang, Qun He, Xuesong Li
Summary: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a genetic syndrome characterized by cutaneous and uterine leiomyomas, as well as an increased risk of developing renal cell carcinoma (RCC). This study identified novel FH mutations in Chinese patients with HLRCC-related RCC, suggesting the importance of germline screening in early-onset cases. The findings provide valuable clinical information for the differential diagnosis of HLRCC-associated RCC.
UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS
(2021)
Article
Pathology
Rahul Mannan, Xiaoming Wang, Pushpinder S. Bawa, Seema Chugh, Anya K. Chinnaiyan, Roshni Rangaswamy, Yuping Zhang, Xuhong Cao, Steven C. Smith, Kiril Trpkov, Sean R. Williamson, Ankur R. Sangoi, Sambit Mohanty, Jesse K. McKenney, Sounak Gupta, Cristina Magi-Galluzzi, Pedram Argani, Adeboye O. Osunkoya, Arul M. Chinnaiyan, Saravana M. Dhanasekaran, Rohit Mehra
Summary: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare genetic disease that strongly expresses S-(2-succino)-cysteine (2SC) with limited nuclear positivity. The use of 2SC and loss of FH expression by anti-FH IHC staining can be a comprehensive IHC panel for identifying and differentiating FH-deficient RCC from similar entities.
Article
Chemistry, Analytical
Ying Liu, Yu-Nan Chen, Jie Cheng, Jin-Xin Yan, Chen-Yu Xue, Hui-Yu Pan, Xu-Yang Shen, Jiang Zhou, Peng Jiang, Ying-Lin Zhou, Xin-Xiang Zhang
Summary: An efficient quantification method based on ethanol/acetyl chloride chemical derivatization was developed in this study to detect the overall concentration of 2SC in fumarate accumulation cells quantitatively. The three carboxyl groups of 2SC were esterified to increase hydrophobicity, greatly improving its ionization efficiency. The sensitivity was increased by 112 times; the limit of detection was reduced to 0.885 fmol, and the protein usage was reduced by at least 10 times.
ANALYTICAL CHEMISTRY
(2022)
Article
Pathology
William J. Anderson, Harrison K. Tsai, Lynette M. Sholl, Michelle S. Hirsch
Summary: This study investigates the FH mutational status of FH-deficient RCC with heterogeneous FH loss and complete FH loss, and characterizes additional genetic drivers. The study also evaluates the use of 2SC immunohistochemistry in this setting.
INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY
(2022)
Article
Genetics & Heredity
Yue Shi, Yan Xu, Yiqing Chen, Xiaojun Ren, Yu Kang, Chao Wang
Summary: HLRCC syndrome is a hereditary cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma. In this study, we identified a missense variant in the FH gene that has not been reported before and confirmed its pathogenicity in uterine leiomyomas through in vitro experiments. This variant was classified as likely pathogenic according to the ACMG guideline.
Article
Oncology
Jack P. Gleeson, Ines Nikolovski, Renzo Dinatale, Mark Zucker, Andrea Knezevic, Sujata Patil, Yasser Ged, Ritesh R. Kotecha, Natalie Shapnik, Samuel Murray, Paul Russo, Jonathan Coleman, Chung Han Lee, Zsofia K. Stadler, A. Ari Hakimi, Darren R. Feldman, Robert J. Motzer, Ed Reznik, Martin H. Voss, Ying-Bei Chen, Maria Carlo
Summary: Although most FH-RCC tumors are caused by germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, including NF2 mutations, low tumor mutational burden, and high fraction of genome altered.
CLINICAL CANCER RESEARCH
(2021)
Article
Anatomy & Morphology
Aysel Bayram, Sidar Bagbudar, Hamdullah Sozen, Semen Onder, Ekrem Yavuz
Summary: This study found that morphological assessment of uterine leiomyomas can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing for early recognition and risk assessment.
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Daniel R. Crooks, Nunziata Maio, Martin Lang, Christopher J. Ricketts, Cathy D. Vocke, Sandeep Gurram, Sevilay Turan, Yun-Young Kim, G. Mariah Cawthon, Ferri Sohelian, Natalia De Val, Ruth M. Pfeiffer, Parthav Jailwala, Mayank Tandon, Bao Tran, Teresa W-M Fan, Andrew N. Lane, Thomas Ried, Darawalee Wangsa, Ashkan A. Malayeri, Maria J. Merino, Youfeng Yang, Jordan L. Meier, Mark W. Ball, Tracey A. Rouault, Ramaprasad Srinivasan, W. Marston Linehan
Summary: Understanding the mechanism of Warburg shift to aerobic glycolysis is essential for defining the metabolic basis of cancer. HLRCC, an aggressive cancer, is characterized by impaired mitochondrial respiratory chain, loss of expression of mtDNA-encoded subunits, and accumulation of fumarate, leading to the promotion of aerobic glycolysis and disease progression. Accumulation of fumarate in HLRCC tumors disrupts mtDNA replication and proofreading, causing loss of respiratory chain components.
Review
Oncology
Andrea Katharina Lindner, Gennadi Tulchiner, Andreas Seeber, Peter J. Siska, Martin Thurnher, Renate Pichler
Summary: This review summarizes the pathogenesis of a rare renal cell carcinoma caused by FH deficiency, focusing on the activation of HIF and promotion of tumor development due to fumarate accumulation. Therapeutic options for this type of cancer and potential targets within FH-deficient cells are also discussed.
FRONTIERS IN ONCOLOGY
(2022)
Article
Obstetrics & Gynecology
Outi Uimari, Anne Ahtikoski, Kati Kampjarvi, Ralf Butzow, Ilkka Y. Jarvela, Markku Ryynanen, Lauri A. Aaltonen, Pia Vahteristo, Outi Kuismin
Summary: HLRCC patients present with early-onset uterine leiomyomas, multiple lesions, and undergo surgical treatment at a younger age. HLRCC leiomyomas show distinctive features in CD34 and Bcl-2 immunohistochemistry.
ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA
(2021)
Article
Cell Biology
Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang
Summary: The depletion of fumarate hydratase (FH) in tumors leads to the accumulation of fumarate in the tumor microenvironment (TME), which inhibits the activation, expansion, and efficacy of CD8+ T cells and enhances malignant proliferative capacity. Fumarate accumulation directly succinates ZAP70 protein in CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses. Increasing FH expression to deplete fumarate enhances the anti-tumor efficacy of anti-CD19 CAR T cells. These findings highlight the role of fumarate in controlling T cell receptor (TCR) signaling and suggest that fumarate depletion could be an important strategy for tumor immunotherapy.
Article
Endocrinology & Metabolism
Ali S. Alzahrani, Meshael Alswailem, Balgees Alghamdi, Hindi Al-Hindi
Summary: This study describes a woman with HLRCC syndrome who presented with aggressive poorly differentiated thyroid cancer. It is the first report to link thyroid cancer with HLRCC syndrome.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Article
Radiology, Nuclear Medicine & Medical Imaging
Ling Yang, Xue-Ming Li, Ya-Jun Hu, Meng-Ni Zhang, Jin Yao, Bin Song
Summary: FH-deficient RCC shows distinct MDCT features compared to pRCC type II, being more common in younger patients and larger in size, with a cystic solid pattern and tendency for metastasis. There is no significant difference in imaging features between germline and somatic mutation subgroups.
KOREAN JOURNAL OF RADIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Xin Ge, Mengdie Li, Jianxing Yin, Zhumei Shi, Yao Fu, Ningwei Zhao, Hongshan Chen, Longxiyu Meng, Xinjian Li, Zhibin Hu, Xiaozhi Zhao, Hongqian Guo, Xu Qian
Summary: This study reveals that fumarate can accumulate in cells lacking fumarate hydratase and activate PI3K/AKT signaling by inhibiting PTEN. Fumarate directly modifies PTEN and impairs its inhibitory effect on the PI3K/AKT pathway. Clinical analysis shows a positive correlation between PTEN modification levels and AKT activation in PRCC2.
Article
Oncology
Yen-Yun Wang, Anupama Vadhan, Ching-Hu Wu, Cheng-Yang Hsu, Yu-Chieh Chen, Yuk-Kwan Chen, Pang-Yu Chen, Hieu D. H. Nguyen, Yu-Chiuan Chang, Shyng-Shiou F. Yuan
Summary: This study found that the expression of fumarase hydratase (FH) is significantly lower in endometrial cancer tissues compared to normal tissues, and this decreased expression is associated with increased tumor size and lymph node metastasis. Further analysis showed that knockdown of FH increases cell proliferation, migration, and invasion abilities, while overexpression of FH decreases these abilities.
Article
Pathology
Chen Yang, Robert S. Cimera, Ruth Aryeequaye, Gowtham Jayakumaran, Judy Sarungbam, Hikmat A. Al-Ahmadie, Anuradha Gopalan, S. Joseph Sirintrapun, Samson W. Fine, Satish K. Tickoo, Jonathan Epstein, Victor E. Reuter, Yanming Zhang, Ying-Bei Chen
Summary: Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma, typically with an indolent course but potentially exhibiting aggressive clinical behavior in some cases. Genomic studies have shown that MTSCCs with aggressive clinical behavior may have evolved through clonal evolution, with CDKN2A/B deletion and additional complex genomic abnormalities playing a role in this process. Recognizing the morphologic presentation and adverse histologic features of high-grade MTSCCs can aid in establishing a definitive diagnosis and stratifying patients for treatment and prognostication.
Article
Pathology
Kiril Trpkov, Sean R. Williamson, Anthony J. Gill, Adebowale J. Adeniran, Abbas Agaimy, Reza Alaghehbandan, Mahul B. Amin, Pedram Argani, Ying-Bei Chen, Liang Cheng, Jonathan Epstein, John C. Cheville, Eva Comperat, Isabela Werneck da Cunha, Jennifer B. Gordetsky, Sounak Gupta, Huiying He, Michelle S. Hirsch, Peter A. Humphrey, Payal Kapur, Fumiyoshi Kojima, Jose Lopez, Fiona Maclean, Cristina Magi-Galluzzi, Jesse K. McKenney, Rohit Mehra, Santosh Menon, George J. Netto, Christopher G. Przybycin, Priya Rao, Qiu Rao, Victor E. Reuter, Rola M. Saleeb, Rajal B. Shah, Steven C. Smith, Satish Tickoo, Maria S. Tretiakova, Lawrence True, Virginie Verkarre, Sara E. Wobker, Ming Zhou, Ondrej Hes
Summary: The Genitourinary Pathology Society conducted a review focusing on recent advances in renal neoplasia, underscoring the importance of both morphology and molecular features for accurate diagnosis. They proposed new criteria for categorizing novel, emerging, and provisional entities in order to clarify the evolving classification of renal neoplasia and reduce the number of unclassifiable cases.
Article
Pathology
Kiril Trpkov, Ondrej Hes, Sean R. Williamson, Adebowale J. Adeniran, Abbas Agaimy, Reza Alaghehbandan, Mahul B. Amin, Pedram Argani, Ying-Bei Chen, Liang Cheng, Jonathan I. Epstein, John C. Cheville, Eva Comperat, Isabela Werneck da Cunha, Jennifer B. Gordetsky, Sounak Gupta, Huiying He, Michelle S. Hirsch, Peter A. Humphrey, Payal Kapur, Fumiyoshi Kojima, Jose I. Lopez, Fiona Maclean, Cristina Magi-Galluzzi, Jesse K. McKenney, Rohit Mehra, Santosh Menon, George J. Netto, Christopher G. Przybycin, Priya Rao, Qiu Rao, Victor E. Reuter, Rola M. Saleeb, Rajal B. Shah, Steven C. Smith, Satish Tickoo, Maria S. Tretiakova, Lawrence True, Virginie Verkarre, Sara E. Wobker, Ming Zhou, Anthony J. Gill
Summary: The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, emphasizing the diagnostic criteria and key prognostic features for different types of renal tumors. They also proposed new nomenclature and classification recommendations for some novel variants.
Correction
Pathology
Kiril Trpkov, Sean R. Williamson, Anthony J. Gill, Adebowale J. Adeniran, Abbas Agaimy, Reza Alaghehbandan, Mahul B. Amin, Pedram Argani, Ying-Bei Chen, Liang Cheng, Jonathan I. Epstein, John C. Cheville, Eva Comperat, Isabela Werneck da Cunha, Jennifer B. Gordetsky, Sounak Gupta, Huiying He, Michelle S. Hirsch, Peter A. Humphrey, Payal Kapur, Fumiyoshi Kojima, Jose I. Lopez, Fiona Maclean, Cristina Magi-Galluzzi, Jesse K. McKenney, Rohit Mehra, Santosh Menon, George J. Netto, Christopher G. Przybycin, Priya Rao, Qiu Rao, Victor E. Reuter, Rola M. Saleeb, Rajal B. Shah, Steven C. Smith, Satish Tickoo, Maria S. Tretiakova, Lawrence True, Virginie Verkarre, Sara E. Wobker, Ming Zhou, Ondrej Hes
Summary: A correction to this paper has been published at https://doi.org/10.1038/s41379-021-00775-0.
Correction
Oncology
Min Yuen Teo, Hikmat Al-Ahmadie, Kenneth Seier, Christopher Tully, Ashley M. Regazzi, Eugene Pietzak, David B. Solit, Satish Tickoo, Victor Reuter, Eugene K. Cha, Harry Herr, Timothy Donahue, Sherri M. Donat, Guido Dalbagni, Bernard H. Bochner, Samuel Funt, Gopakumar V. Iyer, Dean F. Bajorin, Irina Ostrovnaya, Jonathan E. Rosenberg
BRITISH JOURNAL OF CANCER
(2022)
Article
Oncology
Samuel A. Funt, Michael Lattanzi, Karissa Whiting, Hikmat Al-Ahmadie, Colleen Quinlan, Min Yuen Teo, Chung-Han Lee, David Aggen, Danielle Zimmerman, Deaglan McHugh, Arlyn Apollo, Trey D. Durdin, Hong Truong, Jeffrey Kamradt, Maged Khalil, Bradley Lash, Irina Ostrovnaya, Asia S. McCoy, Grace Hettich, Ashley Regazzi, Marwah Jihad, Neha Ratna, Abigail Boswell, Kaitlyn Francese, Yuanquan Yang, Edmund Folefac, Harry W. Herr, S. Machele Donat, Eugene Pietzak, Eugene K. Cha, Timothy F. Donahue, Alvin C. Goh, William C. Huang, Dean F. Bajorin, Gopa Iyer, Bernard H. Bochner, Arjun V. Balar, Amir Mortazavi, Jonathan E. Rosenberg
Summary: Neoadjuvant gemcitabine and cisplatin (GC) plus atezolizumab (A) showed promising efficacy for patients with muscle-invasive bladder cancer (MIBC). The study suggests that this combination therapy warrants further investigation, despite limitations regarding PD-L1 as a predictive biomarker.
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Article
Radiology, Nuclear Medicine & Medical Imaging
Maria Clara Fernandes, Alexander Shoushtari, Mario M. Jr Jr Leitao, M. Herman Chui, Hikmat Al-Ahmadie, Iva Petkovska
Summary: This case presents a 47-year-old woman with acral lentiginous melanoma metastatic to the lungs, brain, and spleen, who also had lower urinary tract symptoms and dark mass removed from her vaginal canal. MRI showed polypoidal lesions in the urinary bladder and endometrium, consistent with the suspected diagnosis of melanoma metastases. Cystoscopy and biopsy confirmed the presence of bladder and endometrial metastatic lesions, which are rare occurrences.
JOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY
(2022)
Article
Pathology
Paari Murugan, Liwei Jia, Renzo G. Dinatale, Melissa Assel, Nicole Benfante, Hikmat A. Al-Ahmadie, Samson W. Fine, Anuradha Gopalan, Judy Sarungbam, S. Joseph Sirintrapun, A. Ari Hakimi, Paul Russo, Ying-Bei Chen, Satish K. Tickoo, Victor E. Reuter
Summary: This study analyzed 199 cases of PRCC with type 1 features and found clinicopathological features associated with outcome, indicating that type 2 features in PRCC with mixed histology represent morphologic variance or clonal evolution.
Article
Multidisciplinary Sciences
Jeppe Sejero Holm, Samuel A. Funt, Annie Borch, Kamilla Kjaergaard Munk, Anne-Mette Bjerregaard, James L. Reading, Colleen Maher, Ashley Regazzi, Phillip Wong, Hikmat Al-Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan De Wolf, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Morten Nielsen, Jonathan E. Rosenberg, Dean F. Bajorin, Sine Reker Hadrup
Summary: This study demonstrates that the expansion of neoantigen-specific CD8(+) T cells can distinguish between patients with controlled disease and progressive disease in metastatic urothelial carcinoma treated with PD-L1 blockade. Furthermore, the peripheral NARTs derived from patients with disease control exhibit specific cell phenotypes and increased CD39 levels, suggesting their association with treatment response.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
W. Kimryn Rathmell, R. Bryan Rumble, Peter J. Van Veldhuizen, Hikmat Al-Ahmadie, Hamid Emamekhoo, Ralph J. Hauke, Alexander Louie, Matthew Milowsky, Ana M. Molina, Tracy L. Rose, Shankar Siva, Nicholas G. Zaorsky, Tian Zhang, Rubina Qamar, Terry M. Kungel, Bryan Lewis, Eric A. Singer
Summary: The article provides recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC), including diagnosis, treatment, and participation in clinical trials.
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Article
Oncology
Gil Redelman-Sidi, Anna Binyamin, Anthony C. Antonelli, Will Catalano, James Bean, Hikmat Al-Ahmadie, Achim A. Jungbluth, Michael S. Glickman
Summary: This study reveals that BCG immunotherapy stimulates tumor-specific T-cell immunity and demonstrates that the activation of this immune response requires tumor cell intrinsic expression of CIITA. However, the specific mechanisms of tumor immunity still need to be determined. The findings suggest that different immunotherapy modalities can be employed based on tumor-intrinsic characteristics.
CANCER IMMUNOLOGY RESEARCH
(2022)
Article
Oncology
Victoria E. Fincke, Mateja E. Krulik, Piyush Joshi, Michael C. Fruhwald, Ying-Bei Chen, Pascal D. Johann
Summary: Renal medullary carcinomas (RMC) are aggressive tumors of the kidneys, characterized by a loss of SMARCB1. In this study, we analyzed the methylation profiles of RMC samples and compared them to other SWARCB1 deficient entities. We also focused on the genes important for nephrogenesis and found hypomethylation and high expression of these genes in RMC. Our findings suggest that RMC is a separate entity with limited similarities to other SWARCB1 deficient tumors, and specific treatment is warranted.
Article
Oncology
Michal Sarfaty, Mahdi Golkaram, Samuel A. A. Funt, Hikmat Al-Ahmadie, Shannon Kaplan, Fan Song, Ashley Regazzi, Vladimir Makarov, Fengshen Kuo, Irina Ostrovnaya, Venkatraman Seshan, Chen Zhao, Benjamin Greenbaum, Li Liu, Jonathan E. E. Rosenberg, Timothy A. A. Chan
Summary: Whole-exome sequencing of tumor samples from 88 patients with advanced bladder cancer treated with immune checkpoint blockade therapy (ICB) revealed genetic variables associated with treatment benefit. These include ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, immune dN/dS ratio, tumor cell purity, neutrophil-to-lymphocyte ratio, and smoking history. Four molecular subtypes were identified that showed differential sensitivity to ICB. The association of these subtypes with clinical benefit was validated in an independent cohort and their correlation with outcome was shown in patients not receiving ICB treatment.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Nima Almassi, Karissa Whiting, Antoun Toubaji, Andrew T. Lenis, Emmet J. Jordan, Helen Won, Ashley M. Regazzi, Ying-Bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Irina Ostrovnaya, Eugene J. Pietzak, Eugene K. Cha, Alvin C. Goh, Timothy F. Donahue, Harry W. Herr, S. Machele Donat, Guido Dalbagni, Bernard H. Bochner, Min Yuen Teo, Samuel A. Funt, Jonathan E. Rosenberg, Victor E. Reuter, Dean F. Bajorin, David B. Solit, Hikmat Al-Ahmadie, Gopa Iyer
Summary: This study compares oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma with glandular differentiation, and unspecified urothelial carcinoma. The study found that bladder and urachal adenocarcinoma have genomic profiles similar to colorectal adenocarcinoma, while urothelial carcinoma with glandular differentiation is more similar to unspecified urothelial carcinoma.
JCO PRECISION ONCOLOGY
(2022)
Article
Oncology
Chung-Han Lee, Martin H. Voss, Maria Isabel Carlo, Ying-Bei Chen, Mark Zucker, Andrea Knezevic, Robert A. Lefkowitz, Natalie Shapnik, Chloe Dadoun, Ed Reznik, Neil J. Shah, Colette Ngozi Owens, Deaglan Joseph McHugh, David Henry Aggen, Andrew Leonard Laccetti, Ritesh Kotecha, Darren R. Feldman, Robert J. Motzer
Summary: Cabozantinib/nivolumab combination therapy shows promising efficacy in non-clear-cell renal cell carcinoma, particularly in variants with prominent papillary features, while the treatment effect is limited in chromophobe RCC.
JOURNAL OF CLINICAL ONCOLOGY
(2022)