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

Abstract

In just the past five 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 pathologic features and genetic pathogenesis of TSC-associated tumours.

Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma

“…TSC1/2 second hits seem even more pivotal as a tumourigenic mechanism in TSC considering that they have been detected in angiofibromas arising in TSC patients [42]. Our demonstration of unique tumour-specific TSC2 deleterious second hits/AI in multiple bilateral RCCs including a high proportion of RCCLS tumours supports the notion that RCCLS may be strongly related to abnormalities of the mTOR pathway [32]. The molecular driver could well be the same in both TSC-associated RCCs and their nonfamilial equivalents, and we hypothesize that mTOR pathway alterations are likely to play a significant role in the tumourigenesis of non-familial RCCLS as well.…”

“…While exhibiting a standard AML immunophenotype, some of these lesions adopt an exclusively leiomyomatous histology [30,31], as seen in the proband and his mother. RCC appears earlier and often multifocally in TSC patients [32], often with concurrent AML [33], but at an incidence of approximately 2%, roughly comparable to that of the general population [34,35]. Interestingly, a TSC2 variant was first reported to be associated with multiple bilateral RCCs by Tyburczy et al in 2015 in two unrelated individuals [17], and it is the exact same variant in TSC2 (p.R905Q) we have detected in three related RCC-affected individuals including one patient with multiple bilateral tumours.…”

“…The TSC2 R905Q pathogenic germline variant seems to have carried an increased RCC risk in the present index case, his mother as well as his sister, particularly regarding RCCLS, which has developed in the first two relatives, including five occurrences in our proband. Genetically speaking, TSC-associated smooth muscle proliferations like AMLs (28/30 tumours) [32,41] as well as more aggressive smooth muscle-rich proliferations such as RCCLS tumours have been shown to result from second hits in TSC1/ 2, as shown by Tyburczy et al on 5/5 fresh frozen RCCs and 6/7 RCCs in total [17]. In the context of the same background TSC2 R905Q pathogenic germline variant, we have been able to reproduce this finding using WES in 5/6 different FFPE RCCs from the index case and his mother.…”

The PI3K Pathway in Human Disease

“…Lymphangioleiomyomatosis (LAM) is a syndrome that occurs almost exclusively in females, and is characterized by the emergence of smooth muscle-like cysts in the lung, and a gradual decline in pulmonary function (Henske and McCormack, 2012; Lam et al, 2017). Most women with LAM are diagnosed with a sporadic form of the disease, in which the parental, disease-causing clone has incurred biallelic loss of function mutations in TSC1 or, in the majority of cases, TSC2 .…”

Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study

“…LAM cells in both sporadic and TSC-LAM have bi-allelic inactivating mutations in either the TSC-1 or more frequently the TSC-2 gene 3. Loss of function of TSC-1/2 leads to constitutive activation of the mechanistic target of rapamycin (mTOR), resulting in altered translation of 5′ cap-dependent genes, uncontrolled proliferation, dependence on autophagy and a metabolic shift toward energy generation by glycolysis 4. Suppression of mTOR signalling in women with LAM is associated with reduced loss of lung function,5–7 reduction in angiomyolipoma volume8–10 and reduced chylous complications 11.…”