PIK3CA c.1634A>G (E545G) Mutation in Breast Cancer

PIK3CA

Phosphatidyl 3-kinases (PI3K) are a family of lipid kinases involved in many cellular processes, including cell growth, proliferation, differentiation, motility, and survival. PI3K is a heterodimer composed of 2 subunits—an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit. The PIK3CA gene encodes p110α, one of the catalytic subunits.

PI3K converts PI(4,5)P2 [Phosphatidylinositol 4,5-bisphosphate] to PI(3,4,5)P3 [Phosphatidylinositol (3,4,5)-trisphosphate] on the inner leaflet of the cell membrane. PI(3,4,5)P3 recruits important downstream signaling proteins, such as AKT, to the cell membrane resulting in increased activity of these proteins.

Mutant PIK3CA has been implicated in the pathogenesis of several cancers, including colon cancer, gliomas, gastric cancer, breast cancer, endometrial cancer, and lung cancer (COSMIC; Samuels et al. 2004)

Figure 1. Schematic of the MAPK and PI3K pathways. . Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

PI3K/AKT1/MTOR

Contributors: Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014), Christine M. Lovly, M.D., Ph.D.

Suggested Citation: Horn, L., W. Pao, C. Lovly. 2015. PIK3CA. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

PIK3CA in Breast Cancer

Somatic mutations in PIK3CA have been found in a substantial fraction of breast cancers (see Table 1). PIK3CA mutations are positive prognostic factors in breast cancer (Cizkova et al. 2012; Janku et al. 2012).

Gene Mutation	Invasive Breast Cancer	Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer	HER2 positive Invasive Breast Cancer	Triple-negative Invasive Breast Cancer
PIK3CA	26% (Saal et al. 2005; Stemke-Hale et al. 2008; O'Brien et al. 2010)	34.5% (Saal et al. 2005; Stemke-Hale et al. 2008)	22–31% (Saal et al. 2005; Stemke-Hale et al. 2008)	8.3% (Stemke-Hale et al. 2008)

These mutations usually occur within two "hotspot" areas within exon 9 (the helical domain) and exon 20 (the kinase domain).

Gene	Exon	Location	Amino Acid Position	Amino Acid Change	Nucleotide Change	Frequency Among PIK3CA-Mutated Breast Cancer (COSMIC)
PIK3CA	9	Helical domain	E542	p.E542K	c.1624G>A	11%
			E545	p.E545K	c.1633G>A	20%
				p.E545Q	c.1633G>C	<1%
				p.E545G	c.1634A>G	<1%
				p.E545V	c.1634A>T	<1%
			Q546	p.Q546K	c.1636C>A	<1%
				p.Q546E	c.1636C>G	<1%
				p.Q546P	c.1637A>C	<1%
				p.Q546R	c.1637A>G	<1%
				p.Q546L	c.1637A>T	<1%
				p.D549N	c.1645G>A	<1%
	20	Kinase Domain	H1047	p.H1047R	c.3140A>G	55%
	20	Kinase Domain	H1047	p.H1047L	c.3140A>T	5%

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. PIK3CA in Breast Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/ (Updated August 28).

Last Updated: August 28, 2015

PIK3CA c.1634A>G (E545G) Mutation in Breast Cancer

Properties
Location of mutation	Helical domain; Exon 10 (coding exon 9)
Frequency of PIK3CA mutations in breast cancer	26% (Saal et al. 2005; Stemke-Hale et al. 2008; O'Brien et al. 2010)
Frequency of E545G mutation among PIK3CA-mutated breast cancers	<1%
Implications for Targeted Therapeutics
Response to PI3K inhibitors	Unknown at this time^a
Response to AKT inhibitors	Unknown at this time
Response to mTOR inhibitors	Unknown at this time
Response to PI3K/mTOR inhibitors	Unknown at this time
Response to HER2 inhibitors (lapatinib)	Unknown at this time
Response to anti-HER2 antibodies (trastuzumab)	Unknown at this time

The E545G mutation results in an amino acid substitution at position 545 in PIK3CA, from a glutamic acid (E) to a glycine (G). This mutation occurs within the highly conserved helical domain (Figure 1). Mutated PIK3CA proteins have increased catalytic activity resulting in enhanced downstream signaling and oncogenic transformation in vitro (Kang, Bader, and Vogt 2005).

^a Multiple PI3K inhibitors, including BYL719, buparlisib (BKM120), taselisib (GDC0032), and GSK2636771, are under investigation in patients with PIK3CA-mutated or PTEN-mutated solid tumors. Results from several trials of buparlisib have been reported: from these trials, it is not apparent that PIK3CA mutation status affects therapeutic efficacy, and, overall, evidence for efficacy has been equivocal (Bendell et al. 2012; Hyman et al. 2015; Mayer et al. 2014). Additional trials of buparlisib as well as trials for other PI3K inhibitors are ongoing.

Figure 1. Schematic of PIK3CA E545G mutation. Functional domains of PIK3CA are depicted.

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2017. PIK3CA c.1634A>G (E545G) Mutation in Breast Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/breast-cancer/pik3ca/13/ (Updated January 13).

Last Updated: January 13, 2017

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