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

Abstract

Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing of affected tissue is useful for diagnosis. Drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat these disorders.

Keywords: Mosaicism; Next-generation sequencing; PIK3CA-related overgrowth spectrum; PTEN hamartoma tumor syndrome; Proteus syndrome; Sirolimus; Tuberous sclerosis complex; mTORC1.

Figure 1

Disorders of the mTORC1 signaling pathway.

Figure 2

Patterns of cutaneous mosaicism. Blaschkoid pattern of an epidermal nevus (A) and checkerboard pattern of a capillary malformation (B) in children with Proteus syndrome. Disseminated (C) and type 1 segmental mosaicism (D,E) in women with tuberous sclerosis complex. Angiofibromas are observed in the left nasal groove (D) but absent from the right in the same individual (E). Written informed consent for patients included in this figure was obtained according to NIH protocols 00-H-0051, 95-H-0186, and/or 82-H-0032 (C-E).

Figure 3

Types of mosaicism in autosomal dominant conditions. Each square represents an individual and ovals represent cells. In disseminated mosaicism, a postzygotic mutation occurs relatively early in development so that mutant cells are scattered amongst normal cells throughout the body. In type 1 segmental mosaicism, a postzygotic mutation occurs that is limited to certain body regions. In type 2 segmental mosaicism, the individual inherits only one functional copy of the gene and late in embryogenesis, a postzygotic mutation occurs, resulting in a region that is nullizygous with accentuated disease.