Multicenter Validation of a 1,550-Gene Expression Profile for Identification of Tumor Tissue of Origin

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 04/2009; 27(15):2503-8. DOI: 10.1200/JCO.2008.17.9762
Source: PubMed


Malignancies found in unexpected locations or with poorly differentiated morphologies can pose a significant challenge for tissue of origin determination. Current histologic and imaging techniques fail to yield definitive identification of the tissue of origin in a significant number of cases. The aim of this study was to validate a predefined 1,550-gene expression profile for this purpose.
Four institutions processed 547 frozen specimens representing 15 tissues of origin using oligonucleotide microarrays. Half of the specimens were metastatic tumors, with the remainder being poorly differentiated and undifferentiated primary cancers chosen to resemble those that present as a clinical challenge.
In this blinded multicenter validation study the 1,550-gene expression profile was highly informative in tissue determination. The study found overall sensitivity (positive percent agreement with reference diagnosis) of 87.8% (95% CI, 84.7% to 90.4%) and overall specificity (negative percent agreement with reference diagnosis) of 99.4% (95% CI, 98.3% to 99.9%). Performance within the subgroup of metastatic tumors (n = 258) was found to be slightly lower than that of the poorly differentiated and undifferentiated primary tumor subgroup, 84.5% and 90.7%, respectively (P = .04). Differences between individual laboratories were not statistically significant.
This study represents the first adequately sized, multicenter validation of a gene-expression profile for tissue of origin determination restricted to poorly differentiated and undifferentiated primary cancers and metastatic tumors. These results indicate that this profile should be a valuable addition or alternative to currently available diagnostic methods for the evaluation of uncertain primary cancers.

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Available from: Maureen Lyons, Oct 05, 2015
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    • "More recently, genomic analysis has focused on mutation identification via resequencing of either a limited set of genes, whole exomes, or whole genomes. In addition, advances in RNA-based technologies, including improved expression arrays and RNA sequencing, have provided more accurate gene expression profiles that have proven particularly useful for tumor classification and prognostication in several anatomic sites and for tissue-of-origin assessment in cases of carcinomas of unknown primary origin (Monzon et al., 2009). Efforts to profile the tumor ''epigenome'' have also been intensifying. "
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    ABSTRACT: Rapidly evolving genome technology has enabled extensive molecular analysis of limited tumor biopsy material, thereby facilitating the broader implementation of personalized cancer medicine. However, genomics-based patient stratification across diverse tumor types is unlikely to supplant tissue-of-origin considerations in addressing clinical needs, including the development and application of novel "rationally targeted" cancer therapies.
    Cell 06/2014; 157(7):1509-14. DOI:10.1016/j.cell.2014.05.027 · 32.24 Impact Factor
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    • "To determine the clinical relevance of YY1 in primary GACs, we examined the protein expression of YY1 in 247 clinical gastric cancer samples. The overexpression of YY1 was not correlated with TNM staging, this result was partly concordant with previous reports that there were no difference for the YY1 expression between primary tumor and metastatic samples [40]. Nevertheless, expression of YY1 associated with diffuse type histology both in early-stage and advanced-stage GACs, suggesting that YY1 might be involved in the occurrence and development of diffuse type GACs. "
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    ABSTRACT: Ying Yang 1 (YY1) is a transcription factor that regulates diverse biological processes and increasing recognized to have important roles in carcinogenesis. The function and clinical significance of YY1 in gastric adenocarcinoma (GAC) have not been elucidated. In this study, the functional role of YY1 in gastric cancer was investigated by MTT proliferation assays, monolayer colony formation, cell cycle analysis, signaling pathway analysis, Western blot analysis and in vivo study through YY1 knockdown or overexpression. Immunohistochemical study with YY1 antibody was performed on tissue microarray consisting of 247 clinical GAC samples. The clinical correlation and prognosis significance were evaluated. YY1 expression was up-regulated in gastric cancer cell lines and primary gastric cancers. Knocking down YY1 by siYY1 inhibited cell growth, inducing G1 phase accumulation and apoptosis. Ectopic YY1 expression enhanced cell proliferation in vitro and in vivo. Knocking down YY1 in gastric cancer cells suppressed proliferation by inhibiting Wnt/beta-catenin pathway, whereas its overexpression exerted oncogenic property by activating Wnt/beta-catenin pathway. In primary GAC samples, YY1 nuclear expression correlated with shorter survival and predicted poor prognosis in early stage GACs. Our data demonstrated that YY1 contributes to gastric carcinogenesis in gastric cancer. In early stage GACs YY1 might serve as a poor prognostic marker and possibly as a potential therapeutic target.
    Journal of Translational Medicine 03/2014; 12(1):80. DOI:10.1186/1479-5876-12-80 · 3.93 Impact Factor
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    • "Earlier studies validating molecular assays for tissue of origin diagnosis used samples from known origins [11,12,17,22,23]. More recently, a number of studies have been performed assessing molecular assays in the relevant clinical setting of real CUP patients [13,24-29]. "
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    ABSTRACT: Background Cancer of unknown or uncertain primary is a major diagnostic and clinical challenge, since identifying the tissue-of-origin of metastases is crucial for selecting optimal treatment. MicroRNAs are a family of non-coding, regulatory RNA molecules that are tissue-specific, with a great potential to be excellent biomarkers. Methods In this study we tested the performance of a microRNA-based assay in formalin-fixed paraffin-embedded samples from 84 CUP patients. Results The microRNA based assay agreed with the clinical diagnosis at presentation in 70% of patients; it agreed with the clinical diagnosis obtained after patient management, taking into account response and outcome data, in 89% of patients; it agreed with the final clinical diagnosis reached with supplemental immunohistochemical stains in 92% of patients, indicating a 22% improvement in agreement from diagnosis at presentation to the final clinical diagnosis. In 18 patients the assay disagreed with the presentation diagnosis and was in agreement with the final clinical diagnosis, which may have resulted in the administration of more effective chemotherapy. In three out of four discordant cases in which supplemental IHC was performed, the IHC results validated the assay’s molecular diagnosis. Conclusions This novel microRNA-based assay shows high accuracy in identifying the final clinical diagnosis in a real life CUP patient cohort and could be a useful tool to facilitate administration of optimal therapy.
    Molecular Cancer 06/2013; 12(1):57. DOI:10.1186/1476-4598-12-57 · 4.26 Impact Factor
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