nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.03.2015 | Original Article – Clinical Oncology

Serum peptide signatures for pancreatic cancer based on mass spectrometry: a comparison to CA19-9 levels and routine imaging techniques

verfasst von: Berit Velstra, Marieke A. Vonk, Bert A. Bonsing, Bart J. Mertens, Simone Nicolardi, Anouck Huijbers, Hans Vasen, André M. Deelder, Wilma E. Mesker, Yuri E. M. van der Burgt, Rob A. E. M. Tollenaar

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 3/2015

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The detection of pancreatic tumors lacks a sensitive and specific diagnostic tool. Mass spectrometry (MS)-based profiling of serum proteins is a promising approach for discovery of new clinical biomarkers or biomarker signatures.

Methods

Serum samples from pancreatic cancer (PC) patients and control individuals were collected and processed using a standardized protocol. Samples were divided in a calibration set (n = 49 PC and 110 controls) and a validation set (n = 39 PC and 75 controls). Peptide profiles were obtained using a combination of automated solid-phase extraction with reversed-phase C18 paramagnetic beads and matrix-assisted laser desorption ionization time-of-flight MS.

Results

Linear discriminant analysis with double cross-validation resulted in a discriminating peptide signature for PC in the calibration set with a sensitivity of 78 % and a specificity of 91 % [area under the curve (AUC) of 92 %]. Classification was validated with a sensitivity of 93 % and a specificity of 100 % (AUC of 98 %), and the results were compared with carbohydrate antigen 19-9 levels and currently available clinical imaging techniques. The ten most discriminating peptide peaks were identified as fragments of proteins involved in the clotting cascade, acute phase response and immunologic response.

Conclusions

In this study, it is shown that MS-based serum peptide profiles can discriminate between PC and control samples. The approach has great potential for high-throughput analysis in surveillance programs and appears to be most promising for patients with an inherited risk for PC, who benefit from more frequent screening.

Aebersold R, Mann M (2003) Mass spectrometry-based proteomics. Nature 422:198–207CrossRefPubMed

Albrethsen J (2007) Reproducibility in protein profiling by MALDI-TOF mass spectrometry. Clin Chem 53:852–858CrossRefPubMed

Bipat S, Phoa SS, van Delden OM, Bossuyt PM, Gouma DJ, Lameris JS, Stoker J (2005) Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr 29:438–445CrossRefPubMed

Bladergroen MR, Derks RJ, Nicolardi S, de Visser B, van Berloo S, van der Burgt YE, Deelder AM (2012) Standardized and automated solid-phase extraction procedures for high-throughput proteomics of body fluids. J Proteomics 77:144–153CrossRefPubMed

Cecconi D, Palmieri M, Donadelli M (2011) Proteomics in pancreatic cancer research. Proteomics 11:816–828CrossRefPubMed

Chen JH, Ni RZ, Xiao MB, Guo JG, Zhou JW (2009) Comparative proteomic analysis of differentially expressed proteins in human pancreatic cancer tissue. Hepatobiliary Pancreat Dis Int 8:193–200PubMed

de Noo ME, Tollenaar RA, Ozalp A, Kuppen PJ, Bladergroen MR, Eilers PH, Deelder AM (2005) Reliability of human serum protein profiles generated with C8 magnetic beads assisted MALDI-TOF mass spectrometry. Anal Chem 77:7232–7241CrossRefPubMed

Deng R, Lu Z, Chen Y, Zhou L, Lu X (2007) Plasma proteomic analysis of pancreatic cancer by 2-dimensional gel electrophoresis. Pancreas 34:310–317CrossRefPubMed

Dewitt J, Devereaux BM, Lehman GA, Sherman S, Imperiale TF (2006) Comparison of endoscopic ultrasound and computed tomography for the preoperative evaluation of pancreatic cancer: a systematic review. Clin Gastroenterol Hepatol 4:717–725CrossRefPubMed

Ehmann M, Felix K, Hartmann D, Schnolzer M, Nees M, Vorderwulbecke S, Bogumil R, Buchler MW, Friess H (2007) Identification of potential markers for the detection of pancreatic cancer through comparative serum protein expression profiling. Pancreas 34:205–214CrossRefPubMed

Ghatnekar O, Andersson R, Svensson M, Persson U, Ringdahl U, Zeilon P, Borrebaeck CA (2013) Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature. Int J Cancer 133:2392–2397CrossRefPubMed

Gianazza E, Chinello C, Mainini V, Cazzaniga M, Squeo V, Albo G, Signorini S, Di Pierro SS, Ferrero S, Nicolardi S, van der Burgt YEM, Deelder AM, Magni F (2012) Alterations of the serum peptidome in renal cell carcinoma discriminating benign and malignant kidney tumors. J Proteomics 5:125–140

Goonetilleke KS, Siriwardena AK (2007) Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 33:266–270CrossRefPubMed

Hansson GC, Zopf D (1985) Biosynthesis of the cancer-associated sialyl-Lea antigen. J Biol Chem 260:9388–9392PubMed

Honda K, Hayashida Y, Umaki T, Okusaka T, Kosuge T, Kikuchi S, Endo M, Tsuchida A, Aoki T, Itoi T, Moriyasu F, Hirohashi S, Yamada T (2005) Possible detection of pancreatic cancer by plasma protein profiling. Cancer Res 65:10613–10622CrossRefPubMed

Hortin GL (2006) The MALDI-TOF mass spectrometric view of the plasma proteome and peptidome. Clin Chem 52:1223–1237CrossRefPubMed

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed

Jimenez CR, El FZ, Knol JC, Hoekman K, Kruyt FA, Giaccone G, Smit AB, Li KW (2007) Automated serum peptide profiling using novel magnetic C18 beads off-line coupled to MALDI-TOF-MS. Proteomics Clin Appl 1:598–604CrossRefPubMed

Kakisaka T, Kondo T, Okano T, Fujii K, Honda K, Endo M, Tsuchida A, Aoki T, Itoi T, Moriyasu F, Yamada T, Kato H, Nishimura T, Todo S, Hirohashi S (2007) Plasma proteomics of pancreatic cancer patients by multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis (2D-DIGE): up-regulation of leucine-rich alpha-2-glycoprotein in pancreatic cancer. J Chromatogr B Analyt Technol Biomed Life Sci 852:257–267CrossRefPubMed

Kojima K, Asmellash S, Klug CA, Grizzle WE, Mobley JA, Christein JD (2008) Applying proteomic-based biomarker tools for the accurate diagnosis of pancreatic cancer. J Gastrointest Surg 12:1683–1690CrossRefPubMed

Koomen JM, Shih LN, Coombes KR, Li D, Xiao LC, Fidler IJ, Abbruzzese JL, Kobayashi R (2005) Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. Clin Cancer Res 11:1110–1118PubMed

Koopmann J, Zhang Z, White N, Rosenzweig J, Fedarko N, Jagannath S, Canto MI, Yeo CJ, Chan DW, Goggins M (2004) Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry. Clin Cancer Res 10:860–868CrossRefPubMed

Liu D, Cao L, Yu J, Que R, Jiang W, Zhou Y, Zhu L (2009) Diagnosis of pancreatic adenocarcinoma using protein chip technology. Pancreatology 9:127–135CrossRefPubMed

Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, Canzian F, Steplowski E, Arslan AA, Gross M, Helzlsouer K, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Amundadottir L, Bingham SA, Boffetta P, Boutron-Ruault MC, Chanock SJ, Clipp S, Hoover RN, Jacobs K, Johnson KC, Kooperberg C, Luo J, Messina C, Palli D, Patel AV, Riboli E, Shu XO, Rodriguez SL, Thomas G, Tjonneland A, Tobias GS, Tong E, Trichopoulos D, Virtamo J, Ye W, Yu K, Zeleniuch-Jacquette A, Bueno-de-Mesquita HB, Stolzenberg-Solomon RZ (2009) Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Am J Epidemiol 170:403–413CrossRefPubMedCentralPubMed

Mertens BJ, de Noo ME, Tollenaar RA, Deelder AM (2006) Mass spectrometry proteomic diagnosis: enacting the double cross-validatory paradigm. J Comput Biol 13:1591–1605CrossRefPubMed

Micames C, Jowell PS, White R, Paulson E, Nelson R, Morse M, Hurwitz H, Pappas T, Tyler D, McGrath K (2003) Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. Gastrointest Endosc 58:690–695CrossRefPubMed

Navaglia F, Fogar P, Basso D, Greco E, Padoan A, Tonidandel L, Fadi E, Zambon CF, Bozzato D, Moz S, Seraglia R, Pedrazzoli S, Plebani M (2009) Pancreatic cancer biomarkers discovery by surface-enhanced laser desorption and ionization time-of-flight mass spectrometry. Clin Chem Lab Med 47:713–723CrossRefPubMed

Nicolardi S, Palmblad M, Dalebout H, Bladergroen M, Tollenaar RA, Deelder AM, van der Burgt YE (2010) Quality control based on isotopic distributions for high-throughput MALDI-TOF and MALDI-FTICR serum peptide profiling. J Am Soc Mass Spectrom 21:1515–1525CrossRefPubMed

Nilsson T, Mann M, Aebersold R, Yates JR III, Bairoch A, Bergeron JJ (2010) Mass spectrometry in high-throughput proteomics: ready for the big time. Nat Methods 7:681–685CrossRefPubMed

Orlando LA, Kulasingam SL, Matchar DB (2004) Meta-analysis: the detection of pancreatic malignancy with positron emission tomography. Aliment Pharmacol Ther 20:1063–1070CrossRefPubMed

Pawa N, Wright JM, Arulampalam TH (2010) Mass spectrometry based proteomic profiling for pancreatic cancer. JOP 11:423–426PubMed

Sener SF, Fremgen A, Menck HR, Winchester DP (1999) Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg 189:1–7CrossRefPubMed

Shen Y, Tolic N, Liu T, Zhao R, Petritis BO, Gritsenko MA, Camp DG, Moore RJ, Purvine SO, Esteva FJ, Smith RD (2010) Blood peptidome-degradome profile of breast cancer. PLoS ONE 5:e13133CrossRefPubMedCentralPubMed

Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236CrossRefPubMed

Sun ZL, Zhu Y, Wang FQ, Chen R, Peng T, Fan ZN, Xu ZK, Miao Y (2007) Serum proteomic-based analysis of pancreatic carcinoma for the identification of potential cancer biomarkers. Biochim Biophys Acta 1774:764–771CrossRefPubMed

Takadate T, Onogawa T, Fukuda T, Motoi F, Suzuki T, Fujii K, Kihara M, Mikami S, Bando Y, Maeda S, Ishida K, Minowa T, Hanagata N, Ohtsuka H, Katayose Y, Egawa S, Nishimura T, Unno M (2013) Novel prognostic protein markers of resectable pancreatic cancer identified by coupled shotgun and targeted proteomics using formalin-fixed paraffin-embedded tissues. Int J Cancer 132:1368–1382CrossRefPubMed

Tiss A, Smith C, Menon U, Jacobs I, Timms JF, Cramer R (2010) A well-characterised peak identification list of MALDI MS profile peaks for human blood serum. Proteomics 10:3388–3392CrossRefPubMed

Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W (2000) Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 87:809–811CrossRefPubMed

Vasen HF, Wasser M, van MA, Tollenaar RA, Konstantinovski M, Gruis NA, Bergman W, Hes FJ, Hommes DW, Offerhaus GJ, Morreau H, Bonsing BA, De Vostot Nederveen Cappel WH (2011) Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation. Gastroenterology 140:850–856CrossRefPubMed

Velstra B, van der Burgt YE, Mertens BJ, Mesker WE, Deelder AM, Tollenaar RA (2012) Improved classification of breast cancer peptide and protein profiles by combining two serum workup procedures. J Cancer Res Clin Oncol 138:1983–1992CrossRefPubMedCentralPubMed

Velstra B, Bonsing BA, Mertens BJ, van der Burgt YE, Huijbers A, Vasen H, Mesker WE, Deelder AM, Tollenaar RA (2013) Detection of pancreatic cancer using serum protein profiling. HPB (Oxford) 15:602–610CrossRef

Yu KH, Rustgi AK, Blair IA (2005) Characterization of proteins in human pancreatic cancer serum using differential gel electrophoresis and tandem mass spectrometry. J Proteome Res 4:1742–1751CrossRefPubMed

Zapico-Muniz E, Farre-Viladrich A, Rico-Santana N, Gonzalez-Sastre F, Mora-Brugues J (2010) Standardized peptidome profiling of human serum for the detection of pancreatic cancer. Pancreas 39:1293–1298CrossRefPubMed

Titel: Serum peptide signatures for pancreatic cancer based on mass spectrometry: a comparison to CA19-9 levels and routine imaging techniques
verfasst von: Berit Velstra
Marieke A. Vonk
Bert A. Bonsing
Bart J. Mertens
Simone Nicolardi
Anouck Huijbers
Hans Vasen
André M. Deelder
Wilma E. Mesker
Yuri E. M. van der Burgt
Rob A. E. M. Tollenaar
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 3/2015
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-014-1812-2

Springer Medizin

Serum peptide signatures for pancreatic cancer based on mass spectrometry: a comparison to CA19-9 levels and routine imaging techniques