Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signalling

Abstract

Recurrent missense mutations of the PIK3CA oncogene are among the most frequent drivers of human cancers. These often lead to constitutive activation of its product p110α, a phosphatidylinositol 3-kinase (PI3K) catalytic subunit. In addition to causing a range of rare and common cancers, the H1047R mutation is also found in affected tissues of a distinct set of congenital tumours and malformations. Collectively termed PIK3CA-related disorders (PRDs), these lead to overgrowth of skin, brain, adipose, connective, musculoskeletal tissues and/or blood and lymphatic vessel components. Vascular malformations are frequently observed in PRD due to cell-autonomous activation of the PI3K signaling pathway within endothelial cells. These, like most muscle, connective tissue and bone, are derived from the embryonic mesoderm. However, important organ systems affected in PRDs are neuroectodermal derivatives. To further examine their development, we drove the most common post-zygotic activating mutation of Pik3ca in neural crest and related embryonic lineages. Effects in cells having once expressed Wnt1, including the brain roofplate and most neural crest, were most dramatic in the head. Outcomes included megalencephaly, cleft secondary palate and more subtle skull anomalies. Surprisingly, Pik3ca-mutant subpopulations of either mesodermal or neural crest origin was associated with widespread vascular anomalies, leading us to incidentally discover previously undescribed lineages that had expressed the transcription factor Egr2 (Krox20) and that may be co-opted in pathogenesis. Schwann cell precursors having transcribed either Krox20 or Sox10 also gave rise to adult-onset vascular tumors and cancers, including melanoma, after Pik3ca activation. These murine phenotypes may aid discovery of new candidate human PRDs affecting craniofacial and vascular smooth muscle development as well as the reciprocal paracrine signaling mechanisms leading to tissue overgrowth.

Competing Interest Statement

The authors have declared no competing interest.