Detection of soluble biomarkers of pancreatic cancer in endoscopic ultrasound-guided fine-needle aspiration samples

Abstract

Background Biomarkers are urgently needed for pancreatic ductal adenocarcinoma (PDAC). Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the cornerstone for diagnosing PDAC. We developed a method for discovery of PDAC biomarkers using the discarded EUS-FNA liquid.

Methods This retrospective study included 58 patients with suspected pancreatic lesions who underwent EUS-FNA. Protein extracts from EUS-FNA liquid were analyzed by mass spectrometry. Proteomic and clinical data were modeled by supervised statistical learning to identify protein markers and clinical variables that distinguish PDAC.

Results Statistical modeling revealed a protein signature for PDAC screening that achieved high sensitivity and specificity (0.92, 95 % confidence interval [CI] 0.79–0.98, and 0.85, 95 %CI 0.67–0.93, respectively). We also developed a protein signature score (PSS) to guide PDAC diagnosis. In combination with patient age, the PSS achieved 100 % certainty in correctly identifying PDAC patients > 54 years. In addition, 3 /4 inconclusive EUS-FNA biopsies were correctly identified using PSS.

Conclusions EUS-FNA-derived fluid is a rich source of PDAC proteins with biomarker potential. The PSS requires further validation and verification of the feasibility of measuring these proteins in patient sera.

• References

• 1 Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2018; 68: 7-30
• 2 Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014; 371: 2140-2141
• 3 Paniccia A, Hosokawa P, Henderson W. et al. Characteristics of 10-year survivors of pancreatic ductal adenocarcinoma. JAMA Surg 2015; 150: 701-710
• 4 Conroy T, Hammel P, Hebbar M. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018; 379: 2395-2406
• 5 Neoptolemos JP, Kleeff J, Michl P. et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018; 15: 333-348
• 6 Korf J, Huinink KD, Posthuma-Trumpie GA. Ultraslow microdialysis and microfiltration for in-line, on-line and off-line monitoring. Trends Biotechnol 2010; 28: 150-158
• 7 Tang H, Donnell ET. Application of a model-based recursive partitioning algorithm to predict crash frequency. Accid Anal Prev 2019; 132: 105274
• 8 Fogh-Andersen N, Altura BM, Altura BT. et al. Composition of interstitial fluid. Clin Chem 1995; 41: 1522-1525
• 9 Gromov P, Gromova I, Olsen CJ. et al. Tumor interstitial fluid – a treasure trove of cancer biomarkers. Biochim Biophys Acta 2013; 1834: 2259-2270
• 10 Pavlou MP, Diamandis EP. The cancer cell secretome: a good source for discovering biomarkers?. J Proteomics 2010; 73: 1896-1906
• 11 Gronborg M, Kristiansen TZ, Iwahori A. et al. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics 2006; 5: 157-171
• 12 Schaaij-Visser TB, de Wit M, Lam SW. et al. The cancer secretome, current status and opportunities in the lung, breast and colorectal cancer context. Biochim Biophys Acta 2013; 1834: 2242-2258
• 13 Farrah T, Deutsch EW, Omenn GS. et al. A high-confidence human plasma proteome reference set with estimated concentrations in PeptideAtlas. Mol Cell Proteomics 2011;
• 14 Dumartin L, Alrawashdeh W, Trabulo SM. et al. ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation. Oncogene 2017; 36: 3094-3103
• 15 Arumugam P, Bhattacharya S, Chin-Aleong J. et al. Expression of polymeric immunoglobulin receptor and stromal activity in pancreatic ductal adenocarcinoma. Pancreatology 2017; 17: 295-302
• 16 Tian C, Clauser KR, Ohlund D. et al. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc Natl Acad Sci U S A 2019; 116: 19609-19618