When, where and which PIK3CA mutations are pathogenic in congenital disorders

Area of Science:

• Genetics
• Developmental Biology
• Pathogenesis

Background:

• PIK3CA encodes the PI3Kα isoform, frequently mutated in cancer.
• Activating PIK3CA mutations cause PIK3CA-related overgrowth spectrum (PROS) disorders with asymmetric tissue overgrowth and vascular involvement.
• In PROS, postzygotic PIK3CA mutations lead to mosaicism and varied phenotypes, with an unexplained tissue overgrowth pattern.

Purpose of the Study:

• To summarize current knowledge on the determinants of PIK3CA-related pathogenesis in PROS.
• To explore intrinsic factors (cell lineage susceptibility, PIK3CA variant bias) and extrinsic factors (environmental modifiers).
• To review PIK3CA-related vascular malformations in PROS.

Main Methods:

• Review of existing literature on PIK3CA mutations in PROS.
• Analysis of intrinsic and extrinsic factors contributing to pathogenesis.
• Focus on vascular manifestations in PROS.

Main Results:

• PIK3CA mutations are a common driver in both PROS and cancer.
• Mosaic PIK3CA mutations during embryonic development cause PROS phenotypes.
• Specific cell lineages and PIK3CA variants influence disease presentation.

Conclusions:

• Understanding PIK3CA mutation determinants in PROS is crucial for unraveling disease onset, progression, and treatment.
• Insights from PROS can inform cancer research due to shared PIK3CA mutations.
• Further research into PIK3CA pathogenesis will impact therapeutic strategies for PROS and related conditions.