Cancer-Associated PIK3CA Mutations in Overgrowth Disorders

Abstract

PIK3CA is one of the most commonly mutated genes in solid cancers. PIK3CA mutations are also found in benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). As in cancer, PIK3CA mutations in PROS arise postzygotically, but unlike in cancer, these mutations arise during embryonic development, with their timing and location critically influencing the resulting disease phenotype. Recent evidence indicates that phosphoinositide 3-kinase (PI3K) pathway inhibitors undergoing trials in cancer can provide a therapy for PROS. Conversely, PROS highlights gaps in our understanding of PI3K's role during embryogenesis and in cancer development. Here, we summarize current knowledge of PROS, evaluate challenges and strategies for disease modeling, and consider the implications of PROS as a paradigm for understanding activating PIK3CA mutations in human development and cancer.

Keywords: PI3K; PIK3CA; cancer; overgrowth syndromes.

Figure 1

Simplified PI3K Signaling Cascade and Known Clinical Disorders Caused by Genetic Pathway Activation. Color coding corresponds to the genetic disorders listed. The numbers of reported cases in the table are approximate. Cancer (C) is used to indicate a known increase in malignancy risk for each disorder. Although cancer itself features complex genetic mosaicism, in this figure ‘mosaic’ (M) is restricted to non-cancer mosaicism. AKT, protein kinase B; FOXO, Forkhead Box O; GSK3, glycogen synthase kinase-3; mTORC, mechanistic target of rapamycin complex; PI3K, phosphoinositide 3-kinase; PI(3,4,5)P₃, phosphatidylinositol-3,4,5-trisphosphate; PI(4,5)P₂, phosphatidylinositol-4,5-bisphosphate; PTEN, phosphatase and tensin homolog.

Figure 2

The Spectra of Activating PIK3CA Mutations in Cancer and PROS. Most (>80%) activating PIK3CA mutations in cancer (top) and PROS (bottom) cluster at three hotspots: two glutamic acid (E) residues at codons 542 and 545, and a histidine (H) residue at codon 1047. The most frequent mutations at these sites introduce a strongly positively charged side chain – lysine (K) at codons 542 and 545 or arginine (R) at codon 1047. With the exception of the RAS-binding domain (RBD), mutations affect the entire p110α protein, including the adaptor-binding domain (ABD), the C2 domain, the helical domain, and the kinase domain. These domains are all required for the inhibitory interactions between p110α and its regulatory subunit. Moreover, the C2 and kinase domains act as lipid-binding interfaces. The distribution of PIK3CA mutations in cancer were obtained from The Catalogue of Somatic Mutations in Cancer (COSMIC, v85, May 2018) , filtered for variants with ≥10 counts (except if also found in PROS). PIK3CA mutations in PROS comprise published cases from larger cohort studies , , , , , . Note that the x-axis is not numerical and thus does not scale to the distance between the indicated residues. PROS, PIK3CA-related overgrowth spectrum.

Figure 3

PROS and Some of Its Constituent Disorders. Many overgrowth disorders previously classified on the basis of anatomical differences are now known to share a common genetic etiology, namely, postzygotic mosaic, activating mutations in PIK3CA. A selection of older descriptors, many of persisting, practical clinical value, is shown in the central word cloud, with approximate frequency of use of the terms indicated by font size. PROS is a more general term proposed to reflect the common genetic etiology of these conditions. Representative images capturing different manifestations of PROS are shown, with the causal PIK3CA mutation in each case indicated below the image. Radiologic images are sections of magnetic resonance images illustrating asymmetric fatty leg overgrowth and infiltrating facial lipomatosis. Hotspot mutations are shown in red. Where people in images are identifiable, informed consent has been gained for publication. References are given for images obtained from published reports , , . CLOVES, congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis syndrome; HHML, hemihypertrophy with multiple lipomatosis; KTS, Klippel–Trenaunay syndrome; MCAP, megalencephaly-capillary malformation syndrome; M-CM, macrocephaly-capillary malformation syndrome; M-CMTC, megalencephaly-cutis marmorata telangiectatica congenita; PROS, PIK3CA-related overgrowth spectrum.

Figure 4

Key Figure: The Phenotypic Effect of Developmental Timing and Location of Founder PIK3CA Mutations Timeline of human embryogenesis postgastrulation, highlighting key patterning events and the development of major organs. The majority of activating PIK3CA mutations in PROS likely arise during this period (D20–D56, gray arrow), which encompasses the development of most organ systems. The embryo is particularly vulnerable to perturbations during this phase. In the subsequent fetal period (D57 to birth), organs formed during embryogenesis grow and differentiate further. The phenotypic heterogeneity in PROS likely reflects the variable timing and location of a PIK3CA mutation during embryogenesis. A mutation arising at early developmental stages is likely to produce disease affecting multiple organ systems. PROS, PIK3CA-related overgrowth spectrum.

Figure 5

Apparent Skewing of Hotspot PIK3CA Mutations toward Some Embryonic Lineages. Shortly after fertilization, the human embryo resembles a flattened cellular disk known as the epiblast. Between 15 and 21 days postfertilization (dpf), the epiblast transforms into the three germ layers (ectoderm, mesoderm, and endoderm) in the process of gastrulation. This involves carefully balanced morphogen gradients and intricate crosstalk among the developing germ layers, acting on one another to instruct lineage specification. The ectoderm gives rise to the epidermis (skin) and nervous system (neuroectoderm), including neural crest derivatives (e.g., cephalic connective tissue). The mesoderm is patterned into three subtypes (shown in the transverse section of the developing embryo), which combined develop into a variety of tissues, including bone, cartilage, connective and adipose tissue, smooth and skeletal muscle, the vascular system, heart, gut and lung walls, blood cells, kidneys, and gonads. The endoderm lineage specifies the gastrointestinal and respiratory systems, the epithelial lining of the bladder and urethra, as well as many endocrine glands. In PROS, it appears that hotspot PIK3CA mutations such as H1047R are not present in endodermal tissue derivatives, and further exhibit a skewing away from blood cells. Note that biopsies from internal organs are rarely available for direct genotyping, and inferences about mutation distribution in such cases are largely based on the macroscopic pattern of overgrowth. PROS, PIK3CA-related overgrowth spectrum.