Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Abstract

Mosaicism is the presence of two or more genetically distinct cell lineages originating from a single zygote. The skin frequently marks mosaic conditions through migration patterns of a population of mutant cells during embryogenesis. Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway can result in segmental overgrowth, hamartomas, and malignant tumors, given the crucial role of this axis in cell growth. Mosaicism for activating mutations in AKT1 and PIK3CA is responsible for Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. These frequently exemplify Happle’s patterns of cutaneous mosaicism. Postzygotic mutations in PTEN and TSC1/TSC2 result in mosaic forms of the PTEN Hamartoma Tumor Syndrome and tuberous sclerosis complex, which may present as disseminated or segmental disease. Distinct features observed in these mosaic conditions may be attributed to differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing methods of affected tissue is often necessary to diagnosis these disorders. Oral mTORC1 inhibitors, such as sirolimus and everolimus, are useful for treating tuberous sclerosis complex, and drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat several of these disorders.

The PI3K Pathway in Human Disease

“…A canonical example of mTORC1-driven disease pathology is tuberous sclerosis, an autosomal, dominantly inherited genetic disorder with a frequency of 1 in 6000 live births (Nathan et al, 2017; Switon et al, 2016). Consistent with the ubiquitous roles of mTORC1 in the stimulation of cell growth and proliferation, tuberous sclerosis is a multi-organ disease characterized by the outgrowth of benign tumors, termed hamartomas, in the brain, kidneys, heart, and other organs.…”

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

“…Germline PTEN mutations have been identified in related syndromes collectively referred to as PTEN hamartoma tumour syndrome (PHTS) 3 4. These disorders include Cowden syndrome (CS; OMIM 158350), Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM 153480) as well as segmental overgrowth seen occasionally in individuals with somatic mosaicism for a pathogenic PTEN mutation 5. In addition, somatic mutations in PTEN have been identified in tissue from a variety of tumours, including breast, brain, prostate, endometrial and melanoma 6 7…”

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

“…Pathogenic germline mutations in PTEN lead to PTEN hamartoma tumor syndrome (PHTS) with susceptibility to multiple tumors as well as vascular malformations. This process is initiated after loss or inactivation of the second (wild type) allele by somatic mutation resulting in increased levels of PIP3 and increased activation of AKT . We found 9 cases (approximately 10% of the cases) with a (likely) pathogenic PTEN mutation, of which at least 4 were a germline mutation, in the retrospective cohort.…”

“…Activating mutations in PIK3CA , AKT1 , and TEK , and alternatively disrupting mutations in PTEN, activate the mTOR pathway, regulating cell growth, proliferation, survival and cell cycle progression . PIK3CA mutations are the most ubiquitous ones in vascular malformations.…”