Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

Xu, Yunze; Kong, Wen; Cao, Ming; Wang, Jieying; Wang, Zaoyu; Zheng, Liang; Wang, Xiaoyu; Cheng, Rong-Rong; Wang, He; Yang, Bo; Dong, Baijun; Pan, Jiahua; Chen, Yonghui; Huang, Jiwei; Jiang, Chen; Zhai, Wei; Li, Fangzhou; Chen, Ruohua; Zhang, Xiang; Wu, Guangyu; Geng, Xueqing; Chen, Jiasheng; An, Hong‐Wei; Yuan, Yazhou; Xu, Tianmin; Chen, Dongning; Lin, Dongdong; Xu, Lieyu; Huang, Kaijun; Peng, Ling; Yu, Yafeng; Tai, Shengcheng; Qi, Honggang; Luo, Kai; Kang, Xiaonan; Wang, Hang; Huang, Yong; Zhang, Jin; Xue, Wei

doi:10.1016/j.eururo.2022.05.029

Cited by 23 publications

(19 citation statements)

References 33 publications

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“…The SHJTUCMRJ study cohort consisted of 252 participants from 16 centers: FH-deficient (FH-MT) RCC patients spanning the full spectrum of stages (stage I, II, III and IV; n=77) were from our established cohort (34); 70 out of 77 FH-MT patients carried germline mutations while 7 were sporadic cases, involving missense, nonsense, frameshift and large-scale deletion. Of all FH-MT patients, 47 were with documented family history (Supplemental Table 1).…”

Section: Clinicopathological Characteristics Of the Renal Cell Carcin...mentioning

confidence: 99%

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Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Zheng¹,

Zhu²,

Sneh³

et al. 2023

Journal of Clinical Investigation

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Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified two tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as outstanding plasma biomarkers for early diagnosis (receiver operating characteristic area under curve (ROCAUC) = 0.98). These two molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

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Section: Clinicopathological Characteristics Of the Renal Cell Carcin...mentioning

confidence: 99%

“…IHC and DNA genetic sequencing were performed to confirm the wild type FH. The FH-deficient (FH-MT) renal cell carcinoma (RCC) included 77 patients from 15 centers were selected from our established cohort (34). Total 77 patients covered 70 germline tumor and 7 sporadic, spanning all stages of tumors.…”

Section: Study Cohortsmentioning

confidence: 99%

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Zheng¹,

Zhu²,

Sneh³

et al. 2023

Journal of Clinical Investigation

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“…Germline mutation in MET can promote hereditary pRCC initiation and progression (31,32). The identification of RCC patients with certain pathogenic germline mutations has important clinical implications, guiding systemic therapy and clinical trial eligibility (16,17,33). Although most studies have investigated the prevalence of germline mutations among patients with RCC and some cancer-predisposition genes involved in the tumorigenesis and tumor progression of RCC have been identified (9,25,34), the genetic basis of some inherited renal cancers has not been clearly elucidated.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma

Feng¹,

Cao²,

Ouyang³

et al. 2023

Transl Androl Urol

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Background: Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance.Methods: Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with

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“…24 Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration and high expression of immune checkpoint molecules. 9,25,26 The current management strategy for FH-deficient RCC is aimed at early detection with intervention. Tumors may appear as complex lesions with a mixture of solid or cystic elements and are frequently infiltrative in appearance.…”

Section: Fumarate Hydratase-deficient Renal Cell Carcinomamentioning

confidence: 99%

Update on Selected High-grade Renal Cell Carcinomas of the Kidney: FH-deficient, ALK-rearranged, and Medullary Carcinomas

Chen

2023

Advances in Anatomic Pathology

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High-grade renal cell carcinoma (RCC), often diagnosed at advanced stages, significantly contributes to renal cancer-related mortality. This review explores the progress in understanding specific subtypes of high-grade RCC, namely fumarate hydratase (FH)-deficient RCC, anaplastic lymphoma kinase (ALK)-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma, all of which are now recognized as molecularly defined entities in the WHO classification system (2022). While these entities each exhibit a morphologic spectrum that overlaps with other high-grade RCC, ancillary tools developed based on their distinctive molecular alterations can help establish a specific diagnosis, underscoring the importance of integrating molecular findings into diagnostic paradigms. It is important to exclude these specific tumor types in cases with similar morphologic spectrum before rendering a diagnosis of high-grade papillary RCC, collecting duct carcinoma, or RCC, NOS. Several gray areas exist within the spectrum of high-grade uncommon types of RCC, necessitating continued research to enhance diagnostic precision and therapeutic options.

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Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

Cited by 23 publications

References 33 publications

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma

Update on Selected High-grade Renal Cell Carcinomas of the Kidney: FH-deficient, ALK-rearranged, and Medullary Carcinomas

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