Unlabelled: We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma.

Conclusion: Our findings have direct implications regarding the identification and management of HLRCC patients.

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http://dx.doi.org/10.1111/cge.13014DOI Listing

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Summary: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition characterized by multiple cutaneous and uterine leiomyomas and renal cell cancer (RCC). HLRCC is caused by germline pathogenic/likely pathogenic (P/LP) variants in the fumarate hydratase (FH) gene on chromosome 1q42.3, encoding the mitochondrial enzyme responsible for the conversion of fumarate to malate in the Krebs cycle.

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Shenzhen Hospital, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a clinically aggressive tumor with high rates of progression and mortality. A wide range of morphological variations has been observed in FH-deficient RCC, initially described as type 2 papillary RCC or unclassified RCC. Here, we report a case of FH-deficient RCC with rare signet ring cells features.

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Article Synopsis
  • - Fumarate hydratase (FH) deficiency is linked to hereditary leiomyomatosis and renal cell carcinoma (RCC), and FH-deficient tumors currently have limited treatment options.
  • - Researchers used an epigenetic-focused guide RNA library to identify the chromodomain helicase DNA binding protein 6 (CHD6) as a key factor promoting the growth of FH-mutated RCC through its interaction with pro-inflammatory enhancers and NF-κB-related transcription.
  • - The study found that a specific degrader (AU-15330) could effectively target CHD6 and inhibit the growth of FH-deficient RCC tumors, revealing potential new therapeutic strategies for these cancers.
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