Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney

Autor: Ming Gao, Ivan Pedrosa, Qinbo Zhou, Spencer D. Barnes, Suneetha Chintalapati, Lin Xu, Payal Kapur, James Brugarolas, Venkat S. Malladi, Midori Mitui, Deyssy Carrillo, Jeffrey Miyata, Dinesh Rakheja, Hua Zhong, Lisa N. Kinch
Rok vydání: 2022
Předmět:
Zdroj: Mod Pathol
ISSN: 0893-3952
DOI: 10.1038/s41379-021-00896-6
Popis: Low-grade Oncocytic Tumor (LOT) of the kidney is a recently described entity with poorly understood pathogenesis. Using next-generation sequencing (NGS) and complementary approaches, we provide insight into its biology. We describe 22 LOT corresponding to 7 patients presenting with a median age of 75 years (range 63–86 years) and male to female ratio 2:5. All 22 tumors demonstrated prototypical microscopic features. Tumors were well circumscribed and solid. They were composed of sheets of tumor cells in compact nests. Tumor cells had eosinophilic cytoplasm, round to oval nuclei (without nuclear membrane irregularities), focal subtle perinuclear halos and occasional binucleation. Sharply delineated edematous stromal islands were often observed. Tumor cells were positive for PAX8, negative for CD117 and exhibited diffuse and strong cytokeratin-7 expression. Six patients presented with pT1 tumors and at a median follow-up of 29 months, 4 patients were alive without recurrence (3 patients had died from unrelated causes). All tumors were originally classified as chromophobe renal cell carcinoma, eosinophilic variant (chRCC-eo). While none of the patients presented with known syndromic features, one patient with multiple bilateral LOTs was subsequently found to have a likely pathogenic germline TSC1 mutation. Somatic, likely activating, mutations in MTOR and RHEB were identified in all other evaluable LOTs. As assessed by phospho-S6 and phospho-4E-BP1, mTOR complex 1 (mTORC1) was activated across all cases but to different extent. MTOR mutant LOT typically exhibited lower levels of mTORC1 activation, possibly related to mTORC1 dimerization and the preservation of a wild-type MTOR copy (retained chromosome 1). Supporting its distinction from related entities, gene expression analyses showed that LOT clustered separately from classic chRCC, chRCC-eo and RO. In summary, converging mTORC1 pathway mutations, mTORC1 complex activation and a distinctive gene expression signature along with characteristic phenotypic features support LOT designation as a distinct entity with both syndromic and non-syndromic cases associated with an indolent course.
Databáze: OpenAIRE
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