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

Abstract

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. At a median follow-up of 29 months, four patients were alive without recurrence (three 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 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.

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Fig. 1: Histologic characteristics of LOT.
Fig. 2: Schematic mapping of mTOR mutations in LOT samples.
Fig. 3: Evaluation of mTORC1 pathway activation in LOT.
Fig. 4: Copy number analysis in LOT.
Fig. 5: RNA-seq-based clustering of LOT, RO, and chRCC.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge the patients whose samples provided the foundation for this study and are grateful to the Kidney Cancer Program and the Clinical Data Warehouse teams for their support and assistance.

Funding

This work was supported by the NIH-sponsored Kidney Cancer SPORE grant (P50CA196516) and endowment from Jan and Bob Pickens Distinguished Professorship in Medical Science and Brock Fund for Medical Science Chair in Pathology.

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Contributions

P.K., H.Z., and J.B. designed and performed the research, analyzed and interpreted data, and wrote the paper. M.G. performed sanger sequencing. P.K. and S.C. performed the pathological review of the cases. H.Z. performed the molecular analysis. M.M., S.B., Q.Z., L.X., J.B., and P.K. helped interpret molecular data. J.M. and D.C. performed IHCs. D.R. and V.M. provided technical support. L.K. provided interpretation of crystal structure. I.P. provided radiologic images and their interpretation. P.K. assembled the clinical data. All authors read and approved the final paper.

Corresponding authors

Correspondence to Payal Kapur or James Brugarolas.

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The study was conducted with approval by the UT Southwestern Medical Center (UTSW) Institutional Review Board (IRB) and according to the Health Insurance Portability and Accountability Act (HIPAA) guidelines (STU 022013-052).

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Kapur, P., Gao, M., Zhong, H. et al. Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney. Mod Pathol 35, 333–343 (2022). https://doi.org/10.1038/s41379-021-00896-6

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