In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3389-3389
Abstract:
Background: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths in the United States by 2030. Most of the PDAC patients are diagnosed with advanced disease, and less than 20% of patients are resectable at the time of diagnosis. The current imaging tools and blood markers (e.g. CA 19-9), are inadequate for early disease detection due to their poor specificity and sensitivity. This highlights the need to develop robust, noninvasive biomarkers for early detection of PDAC. While a large body of literature supports the use of cell-free miRNAs (cf-miRNAs) as potential diagnostic biomarkers in cancer, their tumor specificity is often debatable. Given the emerging evidence that exosomal cargo is a more robust representation of individual tumor types, in this study we sought to explore the diagnostic potential of cf-miRNAs along with exosomal miRNAs (exo-miRNAs), to establish a non-invasive miRNA signature for the early detection of PDAC. Methods: As part of the NCI’s Pancreatic Cancer Detection Consortium (PCDC) funded project, in this study, small RNA-sequencing was performed in exosome and cell-free (cf) samples from a cohort of 57 PDAC cases and 57 non-disease controls. Using rigorous bioinformatic and biostatistical approaches, we prioritized a panel of cf- and exo-miRNAs and evaluated its diagnostic performance in the sequencing-based discovery and validation cohorts. Subsequently, the performance of the discovered miRNA panel was validated using qRT-PCR assays in an independent clinical validation cohort of PDAC patients and non-disease controls (n=48/each group). The results were examined by ROC curve analysis to determine the diagnostic power of the biomarker panel individually and in combination for their ability to discriminate PDAC from controls. Results: The genomewide transcriptomic analyses led to the identification of a panel of 13 cf-miRNA and 17 exo-miRNA candidates. Sequencing validation in an independent cohort revealed that a combined panel of cf and exo-miRNAs exhibited an area under curve (AUC) of 0.89. Subsequent risk score analysis demonstrated that our biomarker signature was also robust in the identification of PDAC patients with early-stage cancers (stage I & II) vs. controls (p & lt;0.001). Moreover, when we combined the miRNA biomarker panel with CA19-9 values, the diagnostic performance was significantly superior when compared to the biomarker panel alone. Finally, the validation efforts in clinical cohorts by qRT-PCR revealed that the combined miRNA panel yielded an impressive accuracy with an AUC of 0.91, and a sensitivity of 0.88 and specificity of 0.87. Conclusions: In conclusion, we report a novel, exosome-based miRNA signature for the early detection of patients with PDAC; which could potentially improve early-detection efforts for this fatal malignancy. Citation Format: Kota Nakamura, Souvick Roy, Zhongxu Zhu, Eunsung Jun, Haiyong Han, Ruben M. Munoz, Satoshi Nishiwada, Geeta Sharma, Derek Cridebring, Frederic Zenhausern, Seungchan Kim, Denise Roe, Sourat Darabi, In Woong Han, Douglas Evans, Suguru Yamada, Michael Demure, Scott A. Celinski, Erkut Borazanci, Susan Tsai, John Bolton, Yasuhiro Kodera, Joon Oh Park, Song Cheol Kim, Xin Wang, Daniel Von Hoff, Ajay Goel. An exosomal miRNA-based liquid biopsy signature for the noninvasive early detection of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3389.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-3389
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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