Molecular classification of nonsmall cell lung cancer using a 4-protein quantitative assay
ABSTRACT The importance of definitive histological subclassification has increased as drug trials have shown benefit associated with histology in nonsmall-cell lung cancer (NSCLC). The acuity of this problem is further exacerbated by the use of minimally invasive cytology samples. Here we describe the development and validation of a 4-protein classifier that differentiates primary lung adenocarcinomas (AC) from squamous cell carcinomas (SCC).
Quantitative immunofluorescence (AQUA) was employed to measure proteins differentially expressed between AC and SCC followed by logistic regression analysis. An objective 4-protein classifier was generated to define likelihood of AC in a training set of 343 patients followed by validation in 2 independent cohorts (n = 197 and n = 235). The assay was then tested on 11 cytology specimens.
Statistical modeling selected thyroid transcription factor 1 (TTF1), CK5, CK13, and epidermal growth factor receptor (EGFR) to generate a weighted classifier and to identify the optimal cutpoint for differentiating AC from SCC. Using the pathologist's final diagnosis as the criterion standard, the molecular test showed a sensitivity of 96% and specificity of 93%. Blinded analysis of the validation sets yielded sensitivity and specificity of 96% and 97%, respectively. Our assay classified the cytology specimens with a specificity of 100% and sensitivity of 87.5%.
Molecular classification of NSCLC using an objective quantitative test can be highly accurate and could be translated into a diagnostic platform for broad clinical application.
SourceAvailable from: Daniel J O'Shannessy[Show abstract] [Hide abstract]
ABSTRACT: Aim: Although agents that target FRA have advanced through clinical trials, comprehensive analyses of FRA expression in epithelial cancers compared with clinical variables and prognosis are limited. Materials & methods: FRA expression was examined in non-small-cell lung cancer (NSCLC), ovarian cancer and endometrial cancer cohorts using AQUA(®) technology. Results: For the NSCLC cohort, FRA expression was significantly higher in adenocarcinoma samples (p < 0.001) than other histologies, and in females (p = 0.003) versus males. High FRA expression was significantly associated with better survival in NSCLC cases (p = 0.01) while significantly and independently associated with worse prognosis in endometrial (p < 0.001) and ovarian cancers (p < 0.001). Conclusion: These studies confirm the prognostic value of FRA in multiple indications. The opposing prognostic effects observed may suggest differential biology.Biomarkers in Medicine 12/2013; 7(6):933-946. DOI:10.2217/bmm.13.85 · 2.86 Impact Factor
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ABSTRACT: Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is one of serious diseases causing death for both men and women. Computer-aided diagnosis and survival prediction of NSCLC, is of great importance in providing assistance to diagnosis and personalize therapy planning for lung cancer patients.BMC Bioinformatics 09/2014; 15(1):310. DOI:10.1186/1471-2105-15-310 · 2.67 Impact Factor
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ABSTRACT: To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma.Scientific Reports 01/2014; 3:3544. DOI:10.1038/srep03544 · 5.08 Impact Factor