P-227A DETAILED IMMUNOHISTOCHEMICAL ANALYSIS OF PI3K/AKT/MTOR PATHWAY IN LUNG CANCER: CORRELATION WITH PIK3CA, AKT1, K-RAS OR PTEN MUTATIONAL STATUS AND CLINICOPATHOLOGICAL FEATURES

Abstract Background: Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question. Methods: Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets. Results: AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours. Conclusions: An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses.

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Alterations of insulin-like growth factor-1 receptor gene copy number and protein expression are common in non-small cell lung cancer

Journal of Clinical Pathology ◽

10.1136/jclinpath-2014-202347 ◽

2014 ◽

Vol 67 (11) ◽

pp. 985-991 ◽

Cited By ~ 10

Author(s):

T N Tran ◽

C I Selinger ◽

B Yu ◽

C C Ng ◽

M R J Kohonen-Corish ◽

...

Keyword(s):

Lung Cancer ◽

Protein Expression ◽

Copy Number ◽

Gene Copy Number ◽

Small Cell ◽

Clinicopathological Features ◽

Gene Copy ◽

Small Cell Lung ◽

Mutational Status ◽

Node Metastases

AimsInsulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase membrane receptor involved in tumourigenesis that may be a potential therapeutic target. We aimed to investigate the incidence and prognostic significance of alterations in IGF1R copy number, and IGF1R protein expression in resected primary non-small cell lung cancer (NSCLC), and lymph node metastases.MethodsIGF1R gene copy number status was evaluated by chromogenic silver in situ hybridisation and IGF1R protein expression was evaluated by immunohistochemistry in tissue microarray sections from a retrospective cohort of 309 surgically resected NSCLCs and results were compared with clinicopathological features, including EGFR and KRAS mutational status and patient survival.ResultsIGF1R gene copy number status was positive (high polysomy or amplification) in 29.2% of NSCLC, and 12.1% exhibited IGF1R gene amplification. High IGF1R expression was found in 28.3%. There was a modest correlation between IGF1R gene copy number and protein expression (r=0.2, p<0.05). Alterations of IGF1R gene copy number and protein expression in primary tumours were significantly associated with alterations in lymph node metastases (p<0.01). High IGF1R gene copy number and protein expression was significantly higher in squamous cell carcinomas (SCC) compared with other subtypes of NSCLC (p<0.05). There were no other associations between IGF1R status and other clinicopathological features including patient age, gender, smoking status, tumour size, stage, grade, EGFR or KRAS mutational status or overall survival.ConclusionsHigh IGF1R gene copy number and protein overexpression are frequent in NSCLC, particularly in SCCs, but they are not prognostically relevant.

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PULMONARY MUCOEPIDERMOID CARCINOMA: DIAGNOSIS AND TREATMENT

Journal of Cancer & Allied Specialties ◽

10.37029/jcas.v3i4.157 ◽

2018 ◽

Vol 3 (4) ◽

Author(s):

Shafaq Maqsood ◽

Umm e Kulsoom

Keyword(s):

Lung Cancer ◽

Case Report ◽

Clinical Picture ◽

Mucoepidermoid Carcinoma ◽

Chemotherapeutic Agent ◽

Malignant Neoplasm ◽

Immunohistochemical Analysis ◽

Clinicopathological Features ◽

Rare Entity

Pulmonary mucoepidermoid carcinoma (MEC) is a rare malignant neoplasm with the clinical picture mimicking infectious aetiologies in most of the patients. Hence, this rare entity poses a great challenge to the pathologist in terms of diagnosis and to the oncologist in terms of treatment. This case report aims to look at the clinicopathological features of pulmonary MEC, the role of immunohistochemical analysis in diagnosis and choice of chemotherapeutic agent. The objective of reporting this case on MEC is not only the rare frequency of this carcinoma but also to highlight the importance of adequate immunohistochemical analysis in establishing the diagnosis.Key words: Lung cancer, mucoepidermoid carcinoma, chemotherapy

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PIK3CA Mutation Correlates With mTOR Pathway Expression But Not Clinical and Pathological Features in Fibro-Adipose Vascular Anomaly (FAVA)

10.21203/rs.3.rs-966735/v1 ◽

2021 ◽

Author(s):

Yumiko Hori ◽

Katsutoshi Hirose ◽

Michio Ozeki ◽

Kenji Hata ◽

Daisuke Motooka ◽

...

Keyword(s):

Direct Sequencing ◽

Venous Malformation ◽

Pik3ca Mutation ◽

Vascular Anomaly ◽

Mtor Pathway ◽

Clinicopathological Features ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Immunohistochemical Expression ◽

Mutational Status

Abstract BackgroundFibro-adipose vascular anomaly (FAVA) is a rare and new entity of vascular anomaly. Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene were identified at a frequency of 62.5% in FAVA cases. The PIK3CA mutations excessively activate mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis, implying that PIK3CA mutations may act as drivers of FAVAs. This study investigated the correlations between PIK3CA mutational status, clinicopathological features and immunohistochemical expression of the mTOR pathway in a series of FAVA.MethodsWe retrospectively evaluated the clinical and pathological findings of five FAVA cases. We performed next-generation sequencing (NGS) with a custom panel of genes associated with the mTOR pathway and genes responsible for other vascular anomalies, direct sequencing and immunohistochemical analysis of the mTOR pathway.ResultsTwo PIK3CA-mutation cases and three PIK3CA-wild-type (wt) cases exhibited similar typical clinical features of FAVA. Histological analysis revealed venous malformation, lymphatic malformation, nerves containing enlarged abnormal vessels and fibrofatty tissue were observed regardless of PIK3CA mutational status. In contrast to clinical and histological findings, the immunohistochemical expression of activated AKT and mTOR that are upstream of the mTOR pathway was detected in abnormal vessels of PIK3CA-mutation cases but not in those of PIK3CA-wt cases. However, activated eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase 1 (S6K1), both of which are downstream effectors of the mTOR pathway, were expressed in abnormal vessels of both PIK3CA-mutation and PIK3CA-wt cases. Furthermore, targeting NGS did not find any common genetic mutations involved in the mTOR pathway among PIK3CA-wt cases.ConclusionThere was no significant association between the presence of PIK3CA mutations and the clinicopathological features of FAVA, suggesting that the PIK3CA gene is not necessarily involved in the onset of FAVA. FAVAs lacking PIK3CA mutations would be caused by other gene mutations that activate 4EBP1 and S6K1.

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Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

Current Respiratory Medicine Reviews ◽

10.2174/1573398x16666200319134739 ◽

2020 ◽

Vol 16 (1) ◽

pp. 5-10

Author(s):

Adrien Costantini ◽

Theodoros Katsikas ◽

Clementine Bostantzoglou

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Standard Of Care ◽

Genetic Alterations ◽

Small Cell ◽

Extensive Literature ◽

Small Cell Lung ◽

Anaplastic Lymphoma ◽

Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

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