Recent Advances in Renal Tumors with TSC/mTOR Pathway Abnormalities in Patients with Tuberous Sclerosis Complex and in the Sporadic Setting

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Aug 26

PMID 37627070

Authors

Payal Kapur

James Brugarolas

Kiril Trpkov

Affiliations

Soon will be listed here.

Abstract

A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.

Citing Articles

Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know.

Monich A, Bissler J, Barreto F J Bras Nefrol. 2024; 46(3):e20240013.

PMID: 38991206 PMC: 11239183. DOI: 10.1590/2175-8239-JBN-2024-0013en.

Eosinophilic Solid and Cystic Renal Cell Carcinoma-A Systematic Review and Meta-Analysis.

Loghin A, Popelea M, Todea-Moga C, Cocuz I, Borda A Int J Mol Sci. 2024; 25(11).

PMID: 38892169 PMC: 11172930. DOI: 10.3390/ijms25115982.

Hereditary Renal Cancer Syndromes.

Yanus G, Kuligina E, Imyanitov E Med Sci (Basel). 2024; 12(1).

PMID: 38390862 PMC: 10885096. DOI: 10.3390/medsci12010012.

References

Salles D, Asrani K, Woo J, Vidotto T, Liu H, Vidal I . GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms. J Pathol. 2022; 257(2):158-171. PMC: 9310781. DOI: 10.1002/path.5875. View

Fingar D, Blenis J . Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004; 23(18):3151-71. DOI: 10.1038/sj.onc.1207542. View

Wagner A, Malinowska-Kolodziej I, Morgan J, Qin W, Fletcher C, Vena N . Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010; 28(5):835-40. PMC: 4810029. DOI: 10.1200/JCO.2009.25.2981. View

Brugarolas J, Lei K, Hurley R, Manning B, Reiling J, Hafen E . Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004; 18(23):2893-904. PMC: 534650. DOI: 10.1101/gad.1256804. View

Wolff N, Kabbani W, Bradley T, Raj G, Watumull L, Brugarolas J . Sirolimus and temsirolimus for epithelioid angiomyolipoma. J Clin Oncol. 2010; 28(5):e65-8. DOI: 10.1200/JCO.2009.26.3061. View

Yang H, Rudge D, Koos J, Vaidialingam B, Yang H, Pavletich N . mTOR kinase structure, mechanism and regulation. Nature. 2013; 497(7448):217-23. PMC: 4512754. DOI: 10.1038/nature12122. View

Giannikou K, Malinowska I, Pugh T, Yan R, Tseng Y, Oh C . Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development. PLoS Genet. 2016; 12(8):e1006242. PMC: 4975391. DOI: 10.1371/journal.pgen.1006242. View

Napolitano G, Di Malta C, Ballabio A . Non-canonical mTORC1 signaling at the lysosome. Trends Cell Biol. 2022; 32(11):920-931. DOI: 10.1016/j.tcb.2022.04.012. View

Amin M, McKenney J, Martignoni G, Campbell S, Pal S, Tickoo S . Low grade oncocytic tumors of the kidney: a clinically relevant approach for the workup and accurate diagnosis. Mod Pathol. 2022; 35(10):1306-1316. DOI: 10.1038/s41379-022-01108-5. View

10.

Asrani K, Woo J, Mendes A, Schaffer E, Vidotto T, Villanueva C . An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss. Nat Commun. 2022; 13(1):6808. PMC: 9649702. DOI: 10.1038/s41467-022-34617-7. View

11.

Rakowski S, Winterkorn E, Paul E, Steele D, Halpern E, Thiele E . Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006; 70(10):1777-82. DOI: 10.1038/sj.ki.5001853. View

12.

Agaram N, Sung Y, Zhang L, Chen C, Chen H, Singer S . Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications. Am J Surg Pathol. 2015; 39(6):813-25. PMC: 4431898. DOI: 10.1097/PAS.0000000000000389. View

13.

Hamieh L, Choueiri T, Ogorek B, Khabibullin D, Rosebrock D, Livitz D . Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma. PLoS Genet. 2018; 14(9):e1007679. PMC: 6181431. DOI: 10.1371/journal.pgen.1007679. View

14.

Tjota M, Wanjari P, Segal J, Antic T . TSC/MTOR-mutated eosinophilic renal tumors are a distinct entity that is CK7+/CK20-/vimentin-: a validation study. Hum Pathol. 2020; 115:84-95. DOI: 10.1016/j.humpath.2020.12.006. View

15.

Seyam R, Bissada N, Kattan S, Mokhtar A, Aslam M, Fahmy W . Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urology. 2008; 72(5):1077-82. DOI: 10.1016/j.urology.2008.07.049. View

16.

Gu Y, Cohn S, Christie A, McKenzie T, Wolff N, Do Q . Modeling Renal Cell Carcinoma in Mice: and Inactivation Drive Tumor Grade. Cancer Discov. 2017; 7(8):900-917. PMC: 5540776. DOI: 10.1158/2159-8290.CD-17-0292. View

17.

Osborne J, Fryer A, Webb D . Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991; 615:125-7. DOI: 10.1111/j.1749-6632.1991.tb37754.x. View

18.

Curatolo P, Bombardieri R, Jozwiak S . Tuberous sclerosis. Lancet. 2008; 372(9639):657-68. DOI: 10.1016/S0140-6736(08)61279-9. View

19.

Carlo M, Hakimi A, Stewart G, Bratslavsky G, Brugarolas J, Chen Y . Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights. Eur Urol. 2019; 76(6):754-764. PMC: 7673107. DOI: 10.1016/j.eururo.2019.06.015. View

20.

Henske E, Neumann H, Scheithauer B, Herbst E, Short M, Kwiatkowski D . Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer. 1995; 13(4):295-8. DOI: 10.1002/gcc.2870130411. View