Abstract
The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid-tumor biopsies from a broad selection of cancer types.Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1. Activating PIK3CA mutations and null PTEN mutations were identified by NGS, and for PTEN, confirmed by IHC.Overall, mTOR-pathway activation was identified in 444/538 (83%) samples representing 40 different cancer types. Functional mutations in either or both PIK3CA and PTEN genes were identified in 173/538 (32%) samples. PIK3CA mutations were identified in 60/538 (11%) samples, PTEN mutations were identified in 155/538 (29%) samples and mutations in both PIK3CA and PTEN were identified in 18/538 (3%) samples. Overall, mTOR-pathway activation was not significantly associated with the PIK3CA and PTEN genotypes. However, all 18 samples with both PIK3CA and PTEN mutations also displayed mTOR-pathway activation (χ2 p=0.0471). Also, out of a total of 95 breast cancer samples, there were 5 breast-cancer samples which did not have mTOR-pathway activation, and all 5 (100%) of these had PIK3CA and PTEN mutations compared to 51/90 (57%) in the breast-cancer samples with mTOR-pathway activation (χ2 p=0.0134). Finally, the percentages of PIK3CA mutations were higher in colorectal-cancer samples which had mTOR-pathway activation (9/27, 33%) than in colorectal-cancer samples without mTOR-pathway activation (6/44; 14%; χ2 p=0.0484).Therefore, tumor-biopsy analyses based on combined mTOR-pathway biomarkers (and combined NGS and IHC assessments) could potentially provide treatment-informative stratification for particular cancer types.
Highlights
The mechanistic target of the rapamycinpathway is frequently activated in human cancers [1, 2].The mTOR pathway acts as a sensor of the availability of www.impactjournals.com/oncotarget through direct phosphorylation of 4E-BP1 to p4E-BP1, and once phosphorylated, p4E-BP1 can no longer bind to eIF4F, a translation initiation factor
Out of a total of 95 breast cancer samples, there were 5 breast-cancer samples which did not have mTOR-pathway activation, and all 5 (100%) of these had PIK3CA and PTEN mutations compared to 51/90 (57%) in the breast-cancer samples with mTORpathway activation (χ2 p=0.0134)
The oncogene PIK3CA coding for the phosphatidylinositol 3-kinase (PI3K) p110α subunit and the tumor suppressor gene PTEN coding for the Phosphatase and Tensin Homolog lie upstream of the mTOR pathway
Summary
The mechanistic target of the rapamycin (mTOR)pathway is frequently activated in human cancers [1, 2].The mTOR pathway acts as a sensor of the availability of www.impactjournals.com/oncotarget through direct phosphorylation of 4E-BP1 to p4E-BP1, and once phosphorylated, p4E-BP1 can no longer bind to eIF4F, a translation initiation factor. High expression of p4E-BP1 has been associated with mTOR-pathway activation and cancer [1, 5,6,7,8,9]. The oncogene PIK3CA coding for the phosphatidylinositol 3-kinase (PI3K) p110α subunit and the tumor suppressor gene PTEN coding for the Phosphatase and Tensin Homolog lie upstream of the mTOR pathway. Activating mutations in PIK3CA or null mutations in PTEN and its loss of expression can lead to mTOR-pathway activation [1, 3, 10,11,12]. Stratification of tumor types by PIK3CA or PTEN mutations or expression, in combination with the mTOR activity status, could provide additional information concerning disease prognosis as well as potential sensitivity or resistance to cancer treatments
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