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      Combined measurement of CA 15-3 with novel autoantibodies improves diagnostic accuracy for breast cancer

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          Abstract

          Objective

          CA 15-3 is a traditional biomarker for advanced breast cancer with limited sensitivity for early stage patients. In order to increase the sensitivity for early detection, in this study, we introduced novel tumor-associated autoantibodies that were measured concurrently with serum CA 15-3 to evaluate their diagnostic advantage in breast cancer.

          Methods

          We investigated a T7 breast cancer complementary deoxyribonucleic acid (cDNA) phage library for tumor-associated antigens using sera from normal and breast cancer patients. Identified novel tumor-associated antigens phage proteins were then used to develop enzyme-linked immunosorbent assays to measure corresponding autoantibodies in 150 breast cancer, 150 normal, and 40 other cancer (non breast) patient serum samples. Meanwhile, the same samples were measured for CA 15-3 concentrations. Receiver operating characteristic curve analysis was used to evaluate the predictive accuracies of single markers as well as combined markers.

          Results

          Sequencing analysis revealed that two phage-expressed proteins were within the open reading frame and had significant homology to proteins heterogeneous nuclear ribonucleoproteins F (hnRNPF) and ferritin heavy chain (FTH1). Autoantibodies against hnRNPF and FTH1 alone were significantly higher in patients than in control serum samples ( P < 0.01), and the area under the curve for hnRNPF and FTH1 alone was 0.73 and 0.69, respectively. However, when the two autoantibody biomarkers were analyzed in combination with serum CA 15-3 values, the area under the curve increased to 0.93, and the optimal sensitivity and specificity became 89.3% and 93.8%, respectively. Further messenger ribonucleic acid (mRNA) analysis showed that hnRNPF and FTH1 were significantly upregulated in tumor tissues.

          Conclusion

          Our results indicated that combined serologic biomarkers of tumor-associated antigens with autoantibodies may improve the diagnostic accuracy of breast cancer.

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          Most cited references 32

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          Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

           S Altschul (1997)
          The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSI-BLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.
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            Cancer statistics, 2007.

            Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
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              American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer.

              To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer. For the 2007 update, an Update Committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. In general, significant health outcomes (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations. Recommendations and Thirteen categories of breast tumor markers were considered, six of which were new for the guideline. The following categories showed evidence of clinical utility and were recommended for use in practice: CA 15-3, CA 27.29, carcinoembryonic antigen, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, urokinase plasminogen activator, plasminogen activator inhibitor 1, and certain multiparameter gene expression assays. Not all applications for these markers were supported, however. The following categories demonstrated insufficient evidence to support routine use in clinical practice: DNA/ploidy by flow cytometry, p53, cathepsin D, cyclin E, proteomics, certain multiparameter assays, detection of bone marrow micrometastases, and circulating tumor cells.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and Therapy
                OncoTargets and therapy
                Dove Medical Press
                1178-6930
                2013
                28 March 2013
                : 6
                : 273-279
                Affiliations
                [1 ]Molecular Medicine Center of Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, People’s Republic of China
                [2 ]Department of Molecular and Cell Biology, Hebei University College of Life Sciences, Baoding, People’s Republic of China
                [3 ]Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA
                Author notes
                Correspondence: Li Zhong Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E Second Street, Pomona, California 91766-1854, USA Tel 1 909 469 8220 Email lzhong@ 123456westernu.edu
                Article
                ott-6-273
                10.2147/OTT.S43122
                3615893
                23569391
                © 2013 Dong et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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