Loss of Phosphatase and Tensin Homolog Protein Expression Is an Independent Poor Prognostic Marker in Lung Adenocarcinoma

Yanagawa, Naoki; Leduc, Charles; Kohler, Derek M.; Saieg, Mauro; John, Thomas; Sykes, Jenna; Yoshimoto, Maisa; Pintilie, Melania; Squire, Jeremy A.; Shepherd, Frances A.; Tsao, Ming‐Sound

doi:10.1097/jto.0b013e3182641d4f

Cited by 48 publications

(48 citation statements)

References 40 publications

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“…Analysis of PTEN alteration in surgically removed prostate cancers has revealed that 86% of tumors retain the gene while protein loss or strong reduction is found at 75% percent frequency (13). Similar observations were made in colorectal and lung cancer (21, 22) where PTEN protein loss is far more frequent than gene/ RNA loss, and in thyroid cancer, endocrine pancreatic tumors, and melanoma where PTEN is often lost from cell nuclei (23-25) (reviewed in (26). These cases mostly exhibit normal RNA levels, suggesting that PTEN protein degradation is a common cause of cancer formation (reviewed in (26).…”

Section: Introductionsupporting

confidence: 62%

Molecular Pathways: PI3K Pathway Phosphatases as Biomarkers for Cancer Prognosis and Therapy

Chen

Nowak

Trotman

2014

Clinical Cancer Research

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Cancer research has seen tremendous changes over the past decade. Fast progress in sequencing technology has afforded us with landmark genetic alterations, which had immediate impact on clinical science and practice by pointing to new kinase targets, such as PI 3-Kinase, the EGF receptor or BRAF. The PI 3-Kinase pathway for growth control has emerged as a prime example for both oncogene activation and tumor suppressor loss in cancer. Here, we discuss how therapy using PI 3-kinase pathway inhibitors could benefit from information on specific phosphatases, which naturally antagonize the kinase targets. This PI 3-Kinase pathway is found mutated in most cancer types, including prostate, breast, colon and brain tumors. The tumor suppressing phosphatases operate at two levels. Lipid level phosphatases, such as PTEN and INPP4b revert PI 3-kinase activity to keep the lipid second messengers inactive. At the protein level, PHLPP1/2 protein phosphatases inactivate AKT kinase, thus antagonizing mTOR complex 2 activity. However, in contrast to their kinase counterparts the phosphatases are unlikely drug targets. They would need to be stimulated by therapy and are commonly deleted and mutated in cancer. Yet, since they occupy critical nodes in preventing cancer initiation and progression, the information on their status has tremendous potential in outcome prediction, and in matching the available kinase inhibitor repertoire with the right patients.

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Section: Introductionsupporting

confidence: 62%

Molecular Pathways: PI3K Pathway Phosphatases as Biomarkers for Cancer Prognosis and Therapy

Chen

Nowak

Trotman

2014

Clinical Cancer Research

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“…Although only a limited number of cases were explored by FISH, our data suggest for these cases at least, that PIK3CB amplification is not a clear driver of elevated PI3Kβ expression, and that PTEN deletion is not the cause of PTEN protein loss for all cases. In support of this conclusion, it is reported widely in the literature that although PTEN protein loss is a relatively frequent event in NSCLC, genetic mutations and deletions of this gene are uncommon (33, 3, 34, 35). Furthermore, although epigenetic regulation through promoter hyper-methylation might offer an alternative explanation for regulation of PTEN protein expression, reports suggest that promoter methylation may also not account for all cases of PTEN protein loss in NSCLC (36–38).…”

Section: Discussionmentioning

confidence: 57%

“…Increased pAKT staining has been shown to correlate with more advanced stage of NSCLC disease (17, 24–26); however, no correlation between AKT activation and PTEN expression has been demonstrated in NSCLC to date (17, 40). Despite this, evidence is available to suggest that overexpression of phospho-AKT and loss of PTEN may represent independent indicators of poor prognosis in NSCLC and adenocarcinoma, respectively (15, 35). The expression level of PI3K pathways markers in samples with high PI3Kβ and low PTEN should form the basis of future studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Subset of Human Non–Small Cell Lung Cancer Patients with High PI3Kβ and Low PTEN Expression, More Prevalent in Squamous Cell Carcinoma

Cumberbatch

Tang

Beran

et al. 2014

Clinical Cancer Research

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Purpose The phosphoinositide 3-kinase (PI3K) pathway is a major oncogenic signaling pathway and an attractive target for therapeutic intervention. Signaling through the PI3K pathway is moderated by the tumor suppressor PTEN, which is deficient or mutated in many human cancers. Molecular characterization of the PI3K signaling network has not been well defined in lung cancer; in particular, the role of PI3Kβ and its relation to PTEN in non–small cell lung cancer NSCLC remain unclear. Experimental Design Antibodies directed against PI3Kβ and PTEN were validated and used to examine, by immunohistochemistry, expression in 240 NSCLC resection tissues [tissue microarray (TMA) set 1]. Preliminary observations were extended to an independent set of tissues (TMA set 2) comprising 820 NSCLC patient samples analyzed in a separate laboratory applying the same validated antibodies and staining protocols. The staining intensities for PI3Kβ and PTEN were explored and colocalization of these markers in individual tumor cores were correlated. Results PI3Kβ expression was elevated significantly in squamous cell carcinomas (SCC) compared with adenocarcinomas. In contrast, PTEN loss was greater in SCC than in adenocarcinoma. Detailed correlative analyses of individual patient samples revealed a significantly greater proportion of SCC in TMA set 1 with higher PI3Kβ and lower PTEN expression when compared with adenocarcinoma. These findings were reinforced following independent analyses of TMA set 2. Conclusions We identify for the first time a subset of NSCLC more prevalent in SCC, with elevated expression of PI3Kβ accompanied by a reduction/loss of PTEN, for whom selective PI3Kβ inhibitors may be predicted to achieve greater clinical benefit.

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“…Complete absence of tumor cell staining with positive staining of surrounding tumor stroma fibroblasts/endothelial cells was used to denote PTEN deficiency [5]. …”

Section: Methodsmentioning

confidence: 99%

Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial

et al. 2016

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BackgroundThe clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical “actionability” of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM).MethodsPatients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients’ molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated.ResultsFrom March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response.ConclusionsFew advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate.Trial registration NCT01505400 (date of registration 4 January 2012).Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0364-2) contains supplementary material, which is available to authorized users.

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Loss of Phosphatase and Tensin Homolog Protein Expression Is an Independent Poor Prognostic Marker in Lung Adenocarcinoma

Abstract: Absence of PTEN protein expression is an independent prognostic marker in early-stage resected lung adenocarcinoma.

Cited by 48 publications

References 40 publications

Molecular Pathways: PI3K Pathway Phosphatases as Biomarkers for Cancer Prognosis and Therapy

Molecular Pathways: PI3K Pathway Phosphatases as Biomarkers for Cancer Prognosis and Therapy

Identification of a Subset of Human Non–Small Cell Lung Cancer Patients with High PI3Kβ and Low PTEN Expression, More Prevalent in Squamous Cell Carcinoma

Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial

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