Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC

Gupta, Sounak; Swanson, Amy A.; Chen, Ying-Bei; Lopez, Tilcia; Milošević, Dragana; Kipp, Benjamin R.; Leibovich, Bradley C.; Thompson, R. Houston; Herrera-Hernandez, Loren; Cheville, John C.; Jimenez, Rafael E.

doi:10.1016/j.humpath.2019.07.004

Cited by 66 publications

(55 citation statements)

References 26 publications

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“…The observations in our two patients demonstrate that it is important to detect HLRCC syndrome‐associated RCC because of the high mortality associated with these carcinomas and the potential opportunity for secondary prevention of associated morbidity and mortality in family members 1 . As the incidence of HLRCC syndrome‐associated RCC/FHdRCC cases is very low, it is not feasible to screen all renal cell carcinomas for genetic changes in the FH gene 19,20 . Hence, pathologists need to rely on morphological features that trigger further immunohistochemical and molecular testing.…”

Section: Discussionsupporting

confidence: 86%

“…In accordance with the recommendations for the workup of uterine leiomyomas with FH‐d features, 13,21 we emphasize that retained FH expression does not exclude the presence of a fumarate hydratase deficient RCC. The 2SC antibody has been used in several studies to detect FH deficient RCCs and uterine leiomyomas with high sensitivity 7,19,24,25 . However, as this antibody has only recently been made commercially available, its value for detecting HLRCC patients is yet to be defined.…”

Section: Discussionmentioning

confidence: 99%

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Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach

Wyvekens

Valtcheva

Mischo

et al. 2020

Genes Chromosomes & Cancer

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The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome‐associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome‐associated RCC exhibited an unusual morphology with accumulation of “colloid‐like” cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next‐generation sequencing analyses of HLRCC syndrome‐associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC‐RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome‐associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC ‐ and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome‐associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the “second hit” hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach

Wyvekens

Valtcheva

Mischo

et al. 2020

Genes Chromosomes & Cancer

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“…Gupta et al have recently reported the results of a screening of SDHA/B deficiency in a group of 1009 renal cell neoplasms: SDH-deficient renal cell cancers were detected only in the cases originally classified as oncocytomas (1.1% of these tumors) [ 45 ].…”

Section: Succinate Dehydrogenase (Sdh) and Fumarate Hydratase (Fh)mentioning

confidence: 99%

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

Testa

Castelli

2020

Medicines

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Renal cell cancer (RCC) involves three most recurrent sporadic types: clear-cell RCC (70–75%, CCRCC), papillary RCCC (10–15%, PRCC), and chromophobe RCC (5%, CHRCC). Hereditary cases account for about 5% of all cases of RCC and are caused by germline pathogenic variants. Herein, we review how a better understanding of the molecular biology of RCCs has driven the inception of new diagnostic and therapeutic approaches. Genomic research has identified relevant genetic alterations associated with each RCC subtype. Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments. The understanding of the molecular mechanisms that underlie the development and progression of RCC has considerably expanded treatment options; genomic data might guide treatment options by enabling patients to be matched with therapeutics that specifically target the genetic alterations present in their tumors. These new targeted treatments have led to a moderate improvement of the survival of metastatic RCC patients. Ongoing studies based on the combination of immunotherapeutic agents (immune check inhibitors) with VEGF inhibitors are expected to further improve the survival of these patients.

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“…Functionally, SDH and FH catalyze two consecutive and high-flux reactions in the TCA cycle, and SDH additionally encodes Complex II of the mitochondrial electron transport chain, which is responsible for oxidation of FADH 2 [3]. Both SDHRCC and FHRCC are rare and it is speculated that SDHRCC constitutes 0.05%-0.2% of all RCC diagnoses [4], while FHRCC is comparatively more common but still rare, constituting 0.5-4.35% of all RCC diagnoses [5].…”

Section: Introductionmentioning

confidence: 99%

“…Three recent studies, including one from our group, have described several genetic hallmarks of FHRCC, including characteristically low tumor mutation burden, distinct tumor microenvironments characterized by massive CD8+ T-cell infiltration with PD-L1+ expression in tumors, and a highly depleted and mutant mitochondrial genome [8,13,14]. Prior reports characterizing SDHRCC tumors have largely focused on clinicopathologic hallmarks of the disease and genetic analyses of specific SDH mutant alleles, but have not described the full genomic landscape of SDHRCC [5,15,16]. Hence, comprehensive molecular and metabolomic profiling of SDHRCC tumors has been limited [17].…”

Section: Introductionmentioning

confidence: 99%

Genomic and Metabolic Hallmarks of SDH- and FH-Deficient Renal Cell Carcinomas

Yoo

Tang

Zucker

et al. 2021

Preprint

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PurposeSuccinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of metabolically proximal enzymes. We sought to define and compare the genomic and metabolomic hallmarks of these entities.Experimental DesignWe analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically-confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. Somatic alterations were identified using clinical pipelines, and allele-specific copy number changes were identified using FACETS. Mass-spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors.ResultsForty two patients were analyzed (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCC harbored a germline alteration in SDHB, whereas only 17/22 FHRCC had pathogenic germline FH variants. SDHRCC had a lower mutation burden (p = 0.02) and copy number alteration burden (p = 0.0002) than FHRCC. All SDHRCC presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCC demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCC and FHRCC demonstrated significant, idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC had elevation of numerous acylcarnitines. These characteristic metabolic changes enabled the identification of a previously unrecognized SDH-deficient RCC.ConclusionDespite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities.Translational RelevanceMutations to the TCA cycle enzymes Succinate Dehydrogenase (SDH) and Fumarate Hydratase (FH) predispose individuals to unique subtypes of renal cell carcinoma (SDHRCC and FHRCC, respectively). Defining the genetic and metabolic hallmarks of these diseases is critical for advancing new diagnostic and therapeutic approaches for these rare but biologically intriguing entities. Despite a superficially similar genetic etiology, SDHRCC and FHRCC demonstrated significantly fewer secondary mutations to other cancer-associated genes and copy number aberrations than FHRCC, and was distinguished by universal loss-of-heterozygosity of chromosome 1p. Metabolomic analysis identified pathways disrupted in both SDHRCC and FHRCC, including the massive accumulation of free guanine, as well as pathways uniquely disrupted in each of the two entities. These metabolomic findings enabled the identification of a previously unidentified case of unclassified RCC with SDH deficiency, suggesting that metabolomic profiling may aid in phenotypic classification of tumors and uncover novel therapeutic targets.

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Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC

Cited by 66 publications

References 26 publications

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

Genomic and Metabolic Hallmarks of SDH- and FH-Deficient Renal Cell Carcinomas

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