Functional implications of fumarate-induced cysteine succination.

Mutations in metabolic enzymes are associated with hereditary and sporadic forms of cancer. For example, loss-of-function mutations affecting fumarate hydratase (FH), the tricarboxylic acid (TCA) cycle enzyme, result in the accumulation of millimolar levels of fumarate that cause an aggressive form of kidney cancer. A distinct feature of fumarate is its ability to spontaneously react with thiol groups of cysteines in a chemical reaction termed succination. Although succination of a few proteins has been causally implicated in the molecular features of FH-deficient cancers, the stoichiometry, wider functional consequences, and contribution of succination to disease development remain largely unexplored. We discuss the functional implications of fumarate-induced succination in FH-deficient cells, the available methodologies, and the current challenges in studying this post-translational modification.

Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma.

BACKGROUND: Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors, with each having unique pathologic features. This study investigated the association between prospectively identified suspicious pathology (SP) and FH mutations when patients were referred for genetic testing. METHODS: This was an institutional review board-approved cohort study of patients receiving FH testing from 2008 to 2013. SP was defined as a report of HLRCC histologic features identified during a prospective pathologic assessment. The association between SP and FH mutations was analyzed. RESULTS: FH testing was performed in 29 patients with a median age of 37 years; 15 (52%) were female, and 18 (62%) were white. Pathologists reported SP from kidney tumors (11 of 18), leiomyomas (9 of 15: uterus [n = 8] and bladder [n = 1]), and metastatic tumors (3 of 6) in 23 of 39 associated specimens (59%) from 21 of the 29 patients (72%). Patients with SP were younger (35 vs 51 years; P = .010), and those with kidney tumors more often had stage pT3 or higher renal cell carcinoma than those without SP (100% vs 33%; P = .006). FH mutations were present in 8 patients with SP (38%) and in 1 patient without SP (13%; P = .37); 7 of these patients had kidney cancer (n for SP = 7), all with N1 disease. Analyzing SP by tissue type identified only SP from renal tumors as being significantly associated with positive testing for an FH mutation (P = .013). CONCLUSIONS: SP from kidney tumors was statistically associated with FH mutations. An expert pathologic assessment of renal tumors will facilitate the clinical identification of HLRCC cases, and this will result in genetic testing and targeted cancer screening for patients and at-risk family members. Cancer 2017;123:2452-58. © 2017 American Cancer Society.

Diseases of Hereditary Renal Cell Cancers.

Germline mutations in tumor suppressor genes and oncogenes lead to hereditary renal cell carcinoma (HRCC) diseases, characterized by a high risk of RCC and extrarenal manifestations. Patients of young age, those with a family history of RCC, and/or those with a personal and family history of HRCC-related extrarenal manifestations should be referred for germline testing. Identification of a germline mutation will allow for testing of family members at risk, as well as personalized surveillance programs to detect the early onset of HRCC-related lesions. The latter allows for more targeted and therefore more effective therapy and better preservation of renal parenchyma.

Hereditary leiomyomatosis and renal cell cancer (HLRCC): Case series and review of the literature.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC). HLRCC-related RCC tends to be aggressive. To date, only a few publications have described HLRCC-related RCC, and the clinical, morphological and molecular aspects of HLRCC-related RCC need to be further studied. METHODS: We retrospectively analyzed the clinical and pathological data of 3 patients with HLRCC recently diagnosed. Immunohistochemistry and Whole-exome sequencing was performed on 3 patients. The function of the DNA variant was predicted in silico. RESULTS: We reported 3 patients from unrelated Chinese families, with HLRCC-related RCC and identified 3 different germline FH mutations (2 missense and 1 nonsense). A novel missense mutation of FH gene (c.454A>G, p.N152D) was predicted to be probably pathogenic and deleterious by multiple protein function predicting software. This study indicated that the novel mutation may be responsible for the occurrence of HLRCC-related RCC. 100% (2/2) female RCC patients had uterine fibroids. No cutaneous manifestations were identified. CONCLUSION: We indicate that germline screening should be encouraged in early-onset patients. Clinicopathological data, such as family history and immunohistochemical results can provide valuable clinical information for the differential diagnosis of HLRCC-associated RCC in advance.