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Identi fi cation of Variant-Speci fi c Functions of PIK 3 CA by Rapid Phenotyping of Rare Mutations
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dogruluk, Turgut Tsang, Yiu Huen Espitia, Maribel Chen, Fengju Chen, Tenghui Chong, Zechen Appadurai, Vivek Dogruluk, Armel Eterovic, Agna Karina Bonnen, Penelope E. Creighton, Chad J. Chen, Ken Mills, Gordon B. Scott, Kenneth L. |
| Copyright Year | 2015 |
| Abstract | Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3kinase (PI3K) frequentlymutated in cancer.Orthogonal screening forPIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to5.0% included thosewith andwithout oncogenic activities that ranged fromweak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variantspecific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. Cancer Res; 75(24); 5341–54. 2015 AACR. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/75/24/5341.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
