Dataset Information

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations.

ABSTRACT: Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5502825 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations.

Zhang Yiqun Y Kwok-Shing Ng Patrick P Kucherlapati Melanie M Chen Fengju F Liu Yuexin Y Tsang Yiu Huen YH de Velasco Guillermo G Jeong Kang Jin KJ Akbani Rehan R Hadjipanayis Angela A Pantazi Angeliki A Bristow Christopher A CA Lee Eunjung E Mahadeshwar Harshad S HS Tang Jiabin J Zhang Jianhua J Yang Lixing L Seth Sahil S Lee Semin S Ren Xiaojia X Song Xingzhi X Sun Huandong H Seidman Jonathan J Luquette Lovelace J LJ Xi Ruibin R Chin Lynda L Protopopov Alexei A Westbrook Thomas F TF Shelley Carl Simon CS Choueiri Toni K TK Ittmann Michael M Van Waes Carter C Weinstein John N JN Liang Han H Henske Elizabeth P EP Godwin Andrew K AK Park Peter J PJ Kucherlapati Raju R Scott Kenneth L KL Mills Gordon B GB Kwiatkowski David J DJ Creighton Chad J CJ

Cancer cell 20170518 6

Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream tr ...[more]

PMID: 28528867

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Project description:PurposeOligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression.Experimental designTwo anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.ResultsA specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1 R132H and 1p/19q codeletion) and PIK3CA E542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo-evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.ConclusionsActivation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

Dataset Information

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations.

Publications

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations.

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