Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients

Abstract

Background Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. Methods Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. Results The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. Conclusions These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis

“…Conventionally, this cancer types are considered very difficult to diagnose due to the lack of molecular and prognostic markers and the difficulties in identifying the primary site of origin. Being mostly indolent, they are often already metastatic at diagnosis [ 3 ] and, indeed, selected NEN specimens are being included in clinical studies aiming at tumor origin identification [ 58 ]. Thus, the identification of early and specific diagnostic and prognostic markers as well as novel therapeutic targets is crucial.…”

A Systematic Review of Diagnostic and Prognostic Biomarkers for Head and Neck Cancer of Unknown Primary: An Unmet Clinical Need

“…In addition, we excluded papers for not having HNCUP patient or for using patient data from public databases ( n = 9), for not describing diagnostic or prognostic biomarkers for HNCUP ( n = 4), and finally, for not showing statistically significant data ( n = 4). Finally, the review was performed on a total of 23 studies [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. The flowchart of the systematic search is shown in Figure 3 .…”

“…A 92-gene assay developed by Raghav et al was able to identify the tumor types that are sensitive to ICIs in patients with CUPs, including putative H&N primaries ( n = 1183) [ 26 ]. Another assay based on gene expression quantification was proposed by Sun et al: the 90-gene expression assay identified the primary tumor of CUP patients, and it correctly distinguished the tumor type in 94.4% of specimens, including 31 H&N patients [ 29 ].…”

“…Gene expression panels have been tested for the identification of primaries of CUP patients and were able to predict H&N as primary tumor [ 26 , 29 ]. Focusing on H&N tumors, it was discovered that HNCUPs and the metastasis of known H&N primaries present a different angiogenic phenotype; specifically, HNCUPs seem to present a lower angiogenic phenotype suggesting a worse response to antiangiogenic therapy [ 36 ].…”

“… HPV includes HPV DNA, RNA, and circulating HPV proteins; EBV includes EBV DNA and RNA (EBER and EBER1 RNA). Genetic panel assay: 92- and 90-gene panel assay [ 26 , 29 ]. Ceramides: 16, 18, 24, 24:1; VEGF:VEGF 161, and 165.…”