COL10A1 was identified as a gene with restricted expression in most normal tissues and elevated expression in many diverse tumor types. By contrast, COL10A1 expression was undetectable in the 68 tumor cell lines surveyed in this study. Immunofluorescence studies localized collagen, type X, α-1 (collagen X) staining to tumor vasculature in breast tumors, whereas the vasculature of normal breast tissue was either collagen X-negative or had markedly lower levels. The tumor microenvironment-specific expression of collagen X, together with its localization in the vasculature, may facilitate its use as a novel target for the diagnosis and treatment of diverse solid tumor types.
The scalability of site-specific clonal human embryonic stem cell-derived embryonic progenitor cell lines may provide novel models for the study of differentiation and methods for preparing purified and identified cells types for use in therapy.
The clones E69 and T42 may represent a scalable source of primitive cranial neural crest cells useful in the study of cranial embryology, and potentially cell-based therapy.
e22083 Background: Limitations of current screening mammography, particularly in younger women, demonstrate the need for an alternative breast cancer screening strategy. A non-invasive, easily interpreted and low cost test should address this need. Methods: Gene expression microarray analysis was carried out on 128 individual tumor samples representing over 20 tumor types, 86 samples representing 31 diverse normal tissue types, 68 tumor cell lines and 97 diverse normal primary cell cultures. Genes were ranked for elevated expression in either: i) a large number and variety of tumors relative to normal tissues, or ii) in breast tumors. Elevated expression was verified for a subset of genes using qPCR in a set of independent RNA samples. Proteins coded by genes elevated in breast cancer samples were analyzed in a retrospective training set of breast cancer patient sera samples with cancer-free patient and benign pathology controls using ELISA or bead-based detection assay. Results: Based on availability of suitable reagents, 25 candidate biomarkers were assessed in patient sera samples (31-227 patient samples per biomarker) using ELISA or bead-based assays. Individually, the performance of individual markers varied (ROC AUC, 0.51 - 0.88); however, when expression levels of the best performing markers were combined, the multiplex test demonstrated high-sensitivity (>80%) and specificity (>90%) in identifying early-stage breast cancer patients. Conclusions: A multiplex, proteomic-based approach may provide for a high-performance, blood-based screening diagnostic for breast cancer.
Background: Current breast cancer screening guidelines call for annual mammography for asymptomatic women age 45 to 54 and once every two years for women age 55 and older. Women with suspicious screening mammograms are recommended for a diagnostic mammogram and may also undergo MRI or ultrasound. Ultimately, suspicious findings unresolved by imaging typically result in the recommendation of a breast biopsy. Approximately 10% of suspicious diagnostic mammograms are recommended for breast biopsies and 67% to 95% of these biopsies yield negative results. With the goal of reducing the number of patients with benign pathology undergoing invasive biopsies, we conducted a screen for serum protein biomarkers and identified a novel panel for the non-invasive detection of breast cancer.
Methods: Serum samples were collected at two sites from women with suspicious diagnostic mammogram findings (primarily BI-RADS category 4) undergoing biopsy for the evaluation of a potential malignancy. Serum samples from 100-patients (50 benign pathology and 50 malignant pathology) were evaluated on the SOMAscan Assay 1.3k, which measures levels of 1,310 different protein analytes. Statistical screening methodologies, such as individual t-tests with control for false discovery, were used to identify markers with the potential to distinguish benign from malignant pathology. The candidate markers were further studied and combined using generalized linear modeling to develop three potential diagnostic models. K-fold cross validation was used to guard against over fitting of the models.
Results: A 15-marker model resulted in an AUC of 0.92 with a sensitivity of 90% and specificity of 76%. Two 6-marker models (with 4 markers in common) each resulted in AUC of 0.85, yielding a sensitivity of 90% with a specificity of 56% or 64%.
Conclusions: This study reveals a novel panel of serum protein biomarkers that may allow for the non-invasive and sensitive detection of breast cancer in BI-RADS category 4 patients. A multicenter study is underway to further refine and validate this panel in a larger set of prospectively collected patient samples.
Citation Format: Chapman KB, Copeland K, Kidd J, Qiu L, Sheibani N, Tam O, Friedman L, Korn R, Fiorica J, Lourenco A, Suthers S, Hesterberg L. Development of a panel of serum-based protein biomarkers for the non-invasive detection of breast cancer in BI-RADS category 4 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-05.
Bladder cancer recurrence screening is typically managed with a combination of urine cytology and cystoscopy, each with its inherent caveats. Cystoscopy is generally considered the gold standard for diagnosing bladder cancer and can yield a valuable biopsy, but is too invasive and expensive for routine screening and surveillance. Voided urine cytology is inexpensive and readily available, but lacks the desired level of sensitivity. Furthermore, up to 20% of urine cytology specimens fall into one of two indeterminate categories that require follow-up testing, typically in the form of an invasive cystoscopy procedure. With the goal of developing a urine-based molecular test for bladder cancer recurrence surveillance, we examined gene expression biomarkers in urine cytopathology specimens. 90 patient urine samples were analyzed: 45 high-grade urothelial carcinoma (HG-UC) and 45 benign samples. All patient samples were submitted to the Johns Hopkins Cytopathology Department for evaluation for bladder cancer via urine cytology. The samples represent patients undergoing bladder cancer recurrence screening and patients without a prior history of bladder cancer presenting with hematuria. The urine sediments were stored in liquid based cytology solution at 4°C for a period of 7 - 10 days, during which time the cytopathology diagnosis was determined from a portion of the sample. Post-diagnosis, the pathology sample “leftover” was analyzed for gene expression. RNA was extracted, amplified and microarray analysis was performed and a panel of molecular biomarkers was identified. Individual genes in this panel discriminate between HG-UC and benign in this training set with an average ROC of 0.86 (p <0.0001) while a combined panel of 10 genes yields a ROC of 0.97 (p <0.0001). Differential expression of some of the individual genes from the panel was confirmed by qPCR. Additional evaluation of this gene panel in a validation set is ongoing and results from this validation study will be discussed.
Citation Format: Karen B. Chapman, Liqun Qiu, Jennifer Kidd, Aparna Baxi, Markus D. Lachter, Joseph Wagner, Dorothy L. Rosenthal, Matthew T. Olson. Identification of gene-expression biomarkers in urine pathology specimens for the detection of bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2015-551
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