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  • Writer's pictureDr Edin Hamzić

All About The PIK3CA Gene

Updated: Dec 26, 2022

What is the PIK3CA gene? What does the PIK3CA gene do?

PIK3CA gene, short for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, encodes the p110 alpha (p110α, PI3Kα), which in turn is a catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enzyme [citation].

The phosphatidylinositol 3-kinase (PI3K) enzyme belongs to Class I of PI3Ks enzyme, and there are other types which are:

  • The PIK3CB gene encodes PI3Kβ

  • The PIK3CG gene encodes PI3Kδ

  • The PIK3CD gene encodes PI3Kγ [citation].

Who discovered the PIK3CA gene?

The discovery of the catalytic function of p110α can be attributed to numerous authors and research teams from 1984 to the present. However, the characterization of p110α (together with cloned sequence) is attributed to Hiles et al. in their work [citation].

Where is the PIK3CA gene located? How long is the PIK3CA gene?

The PIK3CA gene is located on chromosome 3, and it is roughly 34 kb long, consisting of 20 exons coding for 1068 amino acids (124 kDa size protein). [citation].

What is the function of the PI3Kα subunit of the PI3K enzyme? Short and simple explanation!

The PI3Kα is a subunit, more precisely catalytic subunit or part, of the PI3K enzyme. But, as I mentioned above, there are other parts of it.

The PI3K is an enzyme that belongs to the family of kinases. Kinases are enzymes that are known for regulating the process of phosphorylation. From the chemical perspective, phosphorylation is simply attaching a phosphate group to another molecule or ion. However, phosphorylation is an essential chemical reaction as it’s the critical element of a cell’s signaling processes. Therefore the PI3Kα subunit is essential for cellular growth and survival in normal and pathological conditions.

What is the function of the PI3Kα subunit of the PI3K enzyme? Long and detailed explanation!

The role of p110 alpha (p110α, PI3Kα) by being a catalytic subunit of the PI3K enzyme means that it helps p110α in the phosphorylation of PtdIns(4,5)P2 coupled with ATP to generate PtdIns(3,4,5)P3 – (PIP3). As we shortly explained, in the process of phosphorylation, the phosphate group is attached to another molecule or ion, and in this case, a phosphate group is attached to PtdIns(4,5)P2 to become PtdIns(3,4,5)P3 – (PIP3). The PIP3 plays a role as a second messenger recruiting cytoplasmic proteins and binding them to the plasma membrane or endomembrane spots [citation]. This transformation of PtdIns(4,5)P2 into PtdIns(3,4,5)P3 – (PIP3) triggers a series of chemical reactions and subsequent signaling that are essential for cellular growth and survival in normal but also pathological conditions.

Like other kinases, the PI3K enzyme is responsible for the phosphorylation of specific signaling molecules; in the case of PI3K, beside above mentioned PtdIns(4,5)P2, there are also PtdIns, PtdIns4P. Moreover, phosphorylation triggers a cascade of other chemical reactions and subsequent signaling, essential in interacting with AKT and mTOR pathways.

The AKT and mTOR pathways are the foundations of much research because they are two pathways essential for cellular growth and survival in normal and also pathological conditions.

This pathway is called the PI3K/AKT/mTOR pathway. Cell signaling is an essential part of intra and inter-cell information systems, and PI3K has involved in numerous signaling processes those yield cell activities, such as cell growth, division (proliferation), movement (migration), new protein production, intra-cells materials transport, cell survival, etc. [citation].

What happens when the PIK3CA gene is mutated?

As it goes with genes in general, they can have mutations that lead to changes in the protein that they encode, changing the protein’s function in different ways by being more or less active or inactive. These protein function changes further cause or can be associated with specific conditions and diseases.

Mutations of the PIK3CA gene can lead to the PI3K enzyme being overactive, with proliferation fueling the growth of cancers, that is, elevated amount of PtdIns-3,4,5-P3 [citation].

Are the PIK3CA gene mutations driver mutations? Is PIK3CA an oncogene or tumor suppressor?

Driver mutations can be of two types depending on what two types of genes are located:

  1. proto-oncogenes or

  2. tumor suppressor genes.

If the gene is a proto-oncogene, such as the PIK3CA gene, the driver mutation must be a gain of function mutation to become tumorigenic. In simple terms, in the case of a proto-oncogene, the driver mutations lead to increased gene function that causes uncontrolled growth and proliferation of cells.

On the other hand, if a gene is a tumor suppressor gene, such as the PTEN gene or the TP53 gene, then the driver mutation must be of anti-proliferative nature leading to the inactivation of the given gene to become tumorigenic. In simple terms, in the case of a tumor suppressor gene, it needs to be turned off in order to cause the uncontrolled growth and proliferation of cells.

Therefore, the PIK3CA gene is an oncogene, and mutations that will lead to gain of function will be tumorigenic [citation].

How does PIK3CA cause cancer?

The PIK3CA mutations cause uncontrolled reactivity of the PI3K enzyme. Remember that PI3K has two subunits, catalytic and regulatory, with mutated PIK3CA gene, which can get overreactive with PtdIns-3,4,5-P3 signaling, thus becoming oncogenic.

Similar disability can happen if the regulatory subunit has a mutation that is unable to prevent excess signaling [citation].

How common are PIK3CA mutations?

In the case of the PIK3CA gene, the p110α protein encoded by PIK3CA genes is involved in the catalytical processes of the PI3K enzyme, namely phosphorylation of PtdIns(4,5)P2 coupled with ATP to generate PtdIns(3,4,5)P3.

Depending on the sample and harboring methods, the PIK3CA mutations in tumors and cancers range from 11–14% collectively and up to 40 % for specific cancers, such as colon, breast, etc.

These numbers vary depending on the study, considering extraction methods, sample size, and other possible indications. Mutations inside breast cancers are the most researched and with the most extensive number of publications up to date. The PIK3CA mutations are found to mutate from 25% to 40% in the case of breast cancers [citation].

What are the mutation hotspots in the PIK3CA gene?

The PIK3CA gene has two main hotspots of mutations:

  • 542/545 region of the helical domain and

  • the 1047 region of the kinase domain (H1047R) [citation].

Is PIK3CA mutation hereditary?

The PIK3CA mutations are somatic (sporadic) mutations, not hereditary [citation], and PIK3CA mutations are considered driver mutations [citation].

What cancers have PIK3CA mutations?

Various cancers have PIK3CA mutations [citation]. PIK3CA mutations, according to search databases, are most often found in breast cancers, as was previously mentioned, in the 20-40%. However, besides breast cancer, PIK3CA is also found in other cancers, such as colon, brain, gastric, lung, ovarian, head and neck squamous cell carcinoma, cholangiocarcinoma, bladder, endometrial, skin, thyroid, cervical, esophageal, liver/biliary cancer, leukemia/lymphoma, neuroblastoma [citation].

What diseases are associated with mutations in the PIK3CA gene?

Mutations in these regions have been associated with the following diseases:

  1. bladder cancer

  2. breast cancer

  3. epidermal nevus

  4. Klipper-Trenaunay syndrome

  5. Megalencephaly-capillary malformation syndrome and other tumor and cancer types [citation].

What causes PIK3CA mutations?

In general, mutations can happen for various reasons, such as errors in DNA replication during cell division, mutagen exposure, or viral infection. PIK3CA mutations are mostly missense mutations with a gain of function for a resulting protein and can be linked to three main hotspots:

  1. Glu-542

  2. Glu-545

  3. His-1047 [citation].

What is PIK3CA wild type?

PIK3CA wild type means no mutations are detected within the PIK3CA gene, resulting in no consequential effect on the resulting protein formation [citation].

How do you test PIK3CA? How do you test for PIK3CA mutation?

The PIK3CA molecular tests can be performed on tissue and plasma specimens, more precisely:

  • Formalin-fixed, paraffin-embedded tissue as a preferred specimen, with validity up to 5 years

  • Other specimens are valid for up to 72 hours and, in the case of negative results, need tissue test conformation. They include:

    • 3ml of bone marrow aspirate in EDTA (lavender top) or sodium heparin (green-top)

    • 5ml of whole blood in an EDTA (lavender top) or sodium heparin (green-top)

Four analytical methods are present for testing PIK3CA mutations found in the literature:

  1. Real-time polymerase chain reaction (RT-PCR, or RT-qPCR) is most often used.

  2. Next-generation sequencing (NGS)

  3. Sanger (direct) sequencing

  4. Liquid Chip Technologies

Recently, a couple of companion tests emerged (the test used to help match a patient to a specific drug or therapy), such as:

  1. FoundationOne®CDx (F1CDx)

  2. FoundationOne®Liquid CDx (Foundation medicine)

  3. Therascreen PIK3CA RGQ Polymerase chain reaction (PCR) kit (QIAGEN. Manchester Ltd), recalled in 2021 due to high frequency of Q546R false positive mutation results [citation]

What is the therascreen PIK3CA RGQ PCR Kit?

The therascreen PIK3CA RGQ PCR Kit is used to detect the following 11 mutations in the PIK3CA gene

  1. Exon 7: C420R

  2. Exon 9:

    1. E542K

    2. E545A

    3. E545D [1635G>T only]

    4. E545G

    5. E545K

    6. Q546E

    7. Q546R

  3. Exon 20:

    1. H1047L

    2. H1047R

    3. H1047Y

The therascreen PIK3CA RGQ PCR Kit is a real-time qualitative PCR test that uses genomic DNA (gDNA) extracted from formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue or circulating tumor DNA (ctDNA) from plasma derived from K2EDTA anticoagulated peripheral whole blood taken from patients with breast cancer.

The test aims to help clinicians detect breast cancer patients who may be eligible for treatment with PIQRAY® (alpelisib) based on detected PIK3CA gene mutations.

Patients whose FFPE tissue or plasma specimen produces a positive therascreen PIK3CA RGQ PCR Kit test result for the presence of one or more of the mentioned PIK3CA mutations are eligible for treatment with PIQRAY® (alpelisib).

Patients whose plasma specimen produces a negative result using this test should be reflexed to testing with FFPE tumor tissue for the presence of PIK3CA mutations.


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