In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity.
In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20.
Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980).
Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions.
In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome.
Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome.
---Variant Function
Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness.
Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity.
