Tumor-biopsy stratification based on mTOR-pathway activity and functional mutations in the upstream genes and .

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 and 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 mutations and null mutations were identified by NGS, and for , 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 and genes were identified in 173/538 (32%) samples. mutations were identified in 60/538 (11%) samples, mutations were identified in 155/538 (29%) samples and mutations in both and were identified in 18/538 (3%) samples. Overall, mTOR-pathway activation was not significantly associated with the and genotypes. However, all 18 samples with both and mutations also displayed mTOR-pathway activation (χ=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 and mutations compared to 51/90 (57%) in the breast-cancer samples with mTOR-pathway activation (=0.0134). Finally, the percentages of 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%; =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.