Mutation and prognostic analyses of <scp>PIK</scp>3<scp>CA</scp> in patients with completely resected lung adenocarcinoma

Song, Zhengbo; Yu, Xinmin; Zhang, Yiping

doi:10.1002/cam4.852

Cited by 24 publications

(24 citation statements)

References 24 publications

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“…There are conflicting reports in the literature about the prognostic value of PIK3CA mutations in solid tumors. While a number of studies have suggested that the presence of a PIK3CA mutation confers a poor prognosis in several cancers including breast, lung and colorectal [30][31][32], other studies have reported no significant difference between patients harbouring PIK3CA mutations and those with wildtype PIK3CA in their tumors [33][34][35], which is consistent with our findings. However, there are currently several ongoing trials targeting PIK3CA mutated tumors with PI3K inhibitors, with some promising results.…”

Section: Discussionsupporting

confidence: 92%

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

et al. 2020

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Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

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Section: Discussionsupporting

confidence: 92%

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

et al. 2020

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“…We first described a large cohort study analyzing niche mutations in adenocarcinoma of the lung and their prognostic role as compared with the more frequently diagnosed mutations. In the current scientific literature, many studies have described the occurrence of general somatic mutations in NSCLC, although some niche mutations, such as c-MET and RET in adenocarcinoma of the lung have been described in a few short reports [19][20][21][22], or in a larger population focusing on a single-niche mutation of PIK3CA [23][24][25]. We took into consideration different rare mutations observed in BRAF, PIK3CA, HER2, and NRAS detected with a total frequency equal to 16.7% of patients with lung adenocarcinoma harboring somatic mutations, which is not a negligible prevalence if transposed to the entire population.…”

Section: Discussionmentioning

confidence: 99%

Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study

et al. 2020

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Objective: In addition to the most common somatic lung cancer mutations (i. e., KRAS and EGFR mutations), other genes may harbor mutations that could be relevant for lung cancer. We defined BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations as "niche" mutations and analyzed. The aim of this retrospective cohort study was to assess the differences in the overall survival (OS) of patients with lung adenocarcinoma harboring niche somatic mutations. Results: Data were gathered for 252 patients. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that 1) niche mutations had a higher mortality than EGFR mutations (HR = 2.3; 95% CI = 1.2-4.4; p = 0.009); 2) KRAS mutations had a higher mortality than EGFR mutations (HR = 2.5; 95% CI = 1.4-4.5; p = 0.003); 3) niche mutations presented a similar mortality to KRAS mutations (HR = 0.9; 95% CI = 0.6-1.5; p = 0.797). Methods: Three cohorts of mutations were selected from patients with lung adenocarcinoma and their OS was compared. Mutations that were searched for, were 1) BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET; 2) K-RAS; and 3) EGFR. Differences in OS between these three cohorts were assessed by means of a multivariable Cox model that adjusted for age, sex, smoking habits, clinical stages, and treatments. Conclusions: Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

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“…In addition, overexpression of PIK3CA has been linked to decreased patient survival; however, there is little known about the role of mutated PIK3CA in HNSCC disease progression (34). Aside from HNSCC, P120CTN loss or PIK3CA mutations correlate with decreased patient survival in many types of cancers (14,(35)(36)(37)(38)(39). At first glance, some cancers, such as colon cancer, show no statistical significance of PIK3CA mutations on patient outcomes (40).…”

Section: Discussionmentioning

confidence: 99%

“…E545K and H1047R mutations account for 90% of these mutations. PIK3CA mutations are associated with decreased survival in many cancers, but their impact on HNSCC has so far been limited to serving as a marker of late stage disease (14)(15)(16). Interestingly, PIK3CA, like P120CTN, is affected by tobacco smoke, the primary risk factor for HNSCC.…”

Section: Introductionmentioning

confidence: 99%

p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC

Kidacki

Lehman

Green

et al. 2017

Molecular Cancer Research

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Despite recent improvements in treatment for head and neck squamous cell carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within 5 years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Because p120-catenin (CTNND1/P120CTN) downregulation and mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion. Furthermore, this study aimed to identify the key effector proteins regulated by P120CTN downregulation and mutations. Studies using oral keratinocytes demonstrated that P120CTN downregulation and mutations increased migration and invasion. In addition, P120CTN downregulation and mutations resulted in elevated matrix metallopeptidase 1 (MMP1) levels. Inhibition of MMP1 resulted in decreased invasion, suggesting that MMP1 plays a critical role in HNSCC invasion. Moreover, analysis of HNSCC patient specimens from The Cancer Genome Atlas confirmed these findings. Tumors with low P120CTN and PI3K pathway mutations have higher levels of MMP1 compared to tumors with high P120CTN and no PI3K pathway mutations. In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC. Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and mutations..

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Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

Cited by 24 publications

References 24 publications

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study

p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC

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