Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and RCC syndrome, which is defined by germline FH gene inactivation. Inactivation of components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss), and subsets of dedifferentiated RCC of clear cell, chromophobe, and papillary types (loss of different SWI/SNF components). FH-RCC and SWI/SNF-deficient RCC share anaplastic nuclear features and highly aggressive course. We analyzed 32 FH-RCCs from 28 patients using 7 commercially available SWI/SNF antibodies (SMARCB1/INI1, SMARCA2, SMARCA4, SMARCC1, SMARCC2, PBRM1, and ARID1A). Variable loss of SMARCB1, ARID1A, and SMARCC1 was observed in 1 of 31, 2 of 31, and 1 of 29 evaluable cases, respectively; 3 of these 4 SWI/SNF-deficient tumors had confirmed FH mutations. No correlation of SWI/SNF loss with solid or sarcomatoid features was observed. Two tumors with SMARCB1 and ARID1A deficiency had available SWI/SNF molecular data; both lacked SMARCB1 and ARID1A mutations. The remaining 5 SWI/SNF components were intact in all cases. Especially PBRM1 seems not to be involved in the pathogenesis or progression of FH-RCC. Our data showed that a subset of FH-RCC (12%) have a variable loss of SWI/SNF complex subunits, likely as secondary genetic events. This should not be confused with SWI/SNF-deficient RCC of other types. Evaluation of FH and SWI/SNF together with comprehensive molecular genetic profiling is needed to explore possible prognostic implications of FH/SWI-SNF double deficiency and to better understand the somatic mutation landscape in high-grade RCC.

Barts Cancer Institute Queen Mary University of London London ECIM 6BQ UK

Calgary Laboratory Services and University of Calgary Calgary Alberta Canada

Charles University and University Hospital Plzen 304 60 Plzen Czech Republic

Cleveland Clinic Cleveland OH 44195 USA

Department of Pathology and Laboratory Medicine University of Tennessee Health Sciences Memphis TN 38103 USA

Department of Pathology VCU School of Medicine Richmond VA 23298 USA

Hospital Cochin 75679 Paris France

Institute of Human Genetics Friedrich Alexander University Erlangen Nürnberg Erlangen Germany

Institute of Pathology Friedrich Alexander University Erlangen Nuremberg University Hospital of Erlangen 91054 Erlangen Germany

Medical College of Wisconsin Milwaukee WI 53226 USA

University of Sydney NSW Australia 2006 Cancer Diagnosis and Pathology Group Kolling Institute Royal North Shore Hospital NSW Australia 2065 and NSW Health Pathology Department of Anatomical Pathology Royal North Shore Hospital St Leonards NSW 2065 Australia

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