Abstract 2814: Angiopoietin-like protein 3 is a novel biomarker and autoantigen in pre-diagnostic sera of non-small cell lung cancer patients
Authors: Taylor Allen D. , Taguchi Ayumu , Ladd Jon , Chao Timothy , Johnson Melissa , Buson Tina , Hanash Samir 
Published: June 2012

Background: Proteomic analyses of mouse lung cancer models have yielded circulating markers that can translate to human disease. Analysis of angiopoietin-like protein 3 (ANGPTL3) in pre-diagnostic human lung cancer sera identified two types of complementary, circulating markers: protein concentration and the occurrence of autoantibodies to ANGPTL3.

Methods: Sera collected up to a year prior to diagnosis of lung cancer from 26 patients and 26 matched healthy controls were analyzed to determine both the circulating concentration of and autoantibody reactivity to ANGPTL3. Circulating levels were measured by commercial enzyme-linked immunosorbent assay (ELISA) and autoantibody reactivity was measured by fluorescent microarray. Additionally, sera from 38 newly diagnosed patients with lung cancer and 38 healthy individuals were also analyzed for ANGPTL3 circulating levels and autoantibody reactivity.

Results: Both ANGPTL3 concentration and autoantibody reactivity were significantly elevated in sera of non-small cell lung cancer (NSCLC) patients collected 0-12 months prior to diagnosis compared to control sera (p=0.12 and p=0.035, respectively). The circulating concentration of ANGPTL3 and autoantibody reactivity were also significantly elevated in the sera of newly diagnosed NSCLC patients compared to control sera (p=0.0039 and p=0.0013, respectively). Autoantibody reactivity to ANGPTL3 and protein concentration in individual patient sera was inversely correlated. A combined analysis of autoantibody reactivity and circulating concentration improved predictive performance by receiver operating characteristic (ROC) analysis compared to individual markers, achieving 53% sensitivity at 90% specificity and an area under the curve of 81%. Western blot analysis showed expression of ANGPTL3 in NSCLC cell lines, but not in an immortalized bronchioepithelial cell line. Immunohistochemical analysis of ANGPTL3 in lung tumor tissue arrays revealed robust staining in the cytoplasm of neoplastic epithelial cells in both adenocarcinomas and squamous cell carcinomas. The addition of ANGPTL3 to a previously published panel of three autoantibodies (i.e. ANXA1, YWHAQ, and LAMR1) for early lung cancer detection improves the predictive performance of the panel to discriminate cases from controls in sera collected prior to the onset of symptoms.

Conclusions: Circulating levels of ANGPTL3 and autoantibody reactivity were significantly elevated in newly diagnosed NSCLC and an independent set of pre-diagnostic samples compared to controls. A combination of circulating levels and autoantibody reactivity for ANGPTL3 improves the predictive performance. ANGPTL3 is strongly expressed in NSCLC cell lines and tissue. Our findings indicate that the occurrence of autoantibodies and the concentration of ANGPTL3 in serum may have utility for the early diagnosis of NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2011-2814