New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex

Abstract

In just the past 5 years, dramatic changes have occurred in the clinical management of tuberous sclerosis complex (TSC). Detailed knowledge about the role of the TSC proteins in regulating the activity of the mammalian target of rapamycin complex 1 (mTORC1) underlies this paradigm-shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in TSC, including pivotal discoveries using next-generation sequencing (NGS). For example, the pathogenesis of angiofibromas is now known to involve UV-induced mutations, and the pathogenesis of multifocal renal cell carcinoma (RCC) in TSC is now known to result from distinct second-hit mutations. In parallel, the pathological features of TSC-associated tumours, including TSC-associated renal cell carcinoma, continue to be defined, despite the fact that TSC was first described 180 years ago. Here, we review recent discoveries related to the pathological features and genetic pathogenesis of TSC-associated tumours. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: angiofibroma; angiomyolipoma (AML); lymphangioleiomyomatosis (LAM); mosaicism; next-generation sequencing (NGS); no mutation identified (NMI); renal cell carcinoma (RCC); tuberous sclerosis complex (TSC).

Figure 1. TSC/mTORC1 signalling and rapamycin

Mutations in TSC1 or TSC2 result in hyperactivation of mTORC1, which in turn results in increased metabolic adaptations that include increased nucleotide synthesis, protein translation and cell growth, in addition to decreased autophagy. Allosteric inhibitors of mTORC1, such as rapamycin are used to restore homeostasis to TSC deficient cells.

Figure 2. Mosaicism in TSC

Recent findings demonstrate that patients with no detectable TSC1 or TSC2 mutation in their peripheral blood cells often have somatic mosaicism. The disease phenotype tends to be milder since not all organs or all cells in an organ have the mutation. The mutation can sometimes be detected at very low levels in the blood. A somatic “second hit” mutation inactivating the wild-type allele is required for tumors to develop.