Skip to main content
Top
Published in: World Journal of Surgery 11/2012

01-11-2012

Prognostic MicroRNAs in Cancer Tissue from Patients Operated for Pancreatic Cancer—Five MicroRNAs in a Prognostic Index

Authors: Nicolai A. Schultz, Klaus K. Andersen, Anne Roslind, Hanni Willenbrock, Morten Wøjdemann, Julia S. Johansen

Published in: World Journal of Surgery | Issue 11/2012

Login to get access

Abstract

Background

The aim of the present study was to identify a panel of microRNAs (miRNAs) that can predict overall survival (OS) in non micro-dissected cancer tissues from patients operated for pancreatic cancer (PC).

Methods

MiRNAs were purified from formalin-fixed paraffin embedded (FFPE) cancer tissue from 225 patients operated for PC. Only a few of those patients received adjuvant chemotherapy. Expressions of miRNAs were determined with the TaqMan MicroRNA Array v2.0. Two statistical methods, univariate selection and the Lasso (Least Absolute Shrinkage and Selection Operator) method, were applied in conjunction with the Cox proportional hazard model to relate miRNAs to OS.

Results

High expression of miR-212 and miR-675 and low expression of miR-148a*, miR-187, and let-7g* predicted short OS independent of age, gender, calendar year of operation, KRAS mutation status, tumor stage, American Society of Anesthesiologists (ASA) score, localization (not miR-148a*), and differentiation of tumor. A prognostic index (PI) based on these five miRNAs was calculated for each patient. The median survival was 1.09 years (Confidence Interval [CI] 0.98–1.43) for PI > median PI compared to 2.23 years (CI 1.84–4.36) for PI < median. MiR-212, miR-675, miR-187, miR-205, miR-944, miR-431, miR-194*, miR-148a*, and miR-769-5p showed the strongest prediction ability by the Lasso method. Thus miR-212, miR-675, miR-187, and miR-148a* were predictors for OS in both statistical methods.

Conclusions

The combination of five miRNAs expression in non micro-dissected FFPE PC tissue can identify patients with short OS after radical surgery. The results are independent of chemotherapy treatment. Patients with a prognostic index > median had a very short median OS of only 1 year.
Appendix
Available only for authorised users
Literature
1.
3.
go back to reference Wagner M, Redaelli C, Lietz M et al (2004) Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 91:586–594PubMedCrossRef Wagner M, Redaelli C, Lietz M et al (2004) Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 91:586–594PubMedCrossRef
4.
go back to reference Beger HG, Thorab FC, Liu Z et al (2004) Pathogenesis and treatment of neoplastic diseases of the papilla of Vater: Kausch-Whipple procedure with lymph node dissection in cancer of the papilla of Vater. J Hepatobiliary Pancreat Surg 11:232–238PubMedCrossRef Beger HG, Thorab FC, Liu Z et al (2004) Pathogenesis and treatment of neoplastic diseases of the papilla of Vater: Kausch-Whipple procedure with lymph node dissection in cancer of the papilla of Vater. J Hepatobiliary Pancreat Surg 11:232–238PubMedCrossRef
5.
go back to reference Bettschart V, Rahman MQ, Engelken FJ et al (2004) Presentation, treatment and outcome in patients with ampullary tumours. Br J Surg 91:1600–1607PubMedCrossRef Bettschart V, Rahman MQ, Engelken FJ et al (2004) Presentation, treatment and outcome in patients with ampullary tumours. Br J Surg 91:1600–1607PubMedCrossRef
6.
go back to reference Locker GY, Hamilton S, Harris J et al (2006) 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24:5313–5327PubMedCrossRef Locker GY, Hamilton S, Harris J et al (2006) 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24:5313–5327PubMedCrossRef
7.
go back to reference Nelson KM, Weiss GJ (2008) MicroRNAs and cancer: past, present and potential future. Mol Cancer Ther 7:3655–3660PubMedCrossRef Nelson KM, Weiss GJ (2008) MicroRNAs and cancer: past, present and potential future. Mol Cancer Ther 7:3655–3660PubMedCrossRef
8.
go back to reference Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55:623–631PubMedCrossRef Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55:623–631PubMedCrossRef
9.
go back to reference Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27:5848–5856PubMedCrossRef Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27:5848–5856PubMedCrossRef
11.
12.
go back to reference Li J, Smyth P, Flavin R et al (2007) Comparison of miRNA expression patterns using total RNA extracted from matched samples of formalin-fixed paraffin-embedded (FFPE) cells and snap frozen cells. BMC Biotechnol 7:36PubMedCrossRef Li J, Smyth P, Flavin R et al (2007) Comparison of miRNA expression patterns using total RNA extracted from matched samples of formalin-fixed paraffin-embedded (FFPE) cells and snap frozen cells. BMC Biotechnol 7:36PubMedCrossRef
13.
go back to reference Zhang X, Chen J, Radcliffe T et al (2008) An array-based analysis of microRNA expression comparing matched frozen and formalin-fixed paraffin-embedded human tissue samples. J Mol Diagn 10:513–519PubMedCrossRef Zhang X, Chen J, Radcliffe T et al (2008) An array-based analysis of microRNA expression comparing matched frozen and formalin-fixed paraffin-embedded human tissue samples. J Mol Diagn 10:513–519PubMedCrossRef
14.
go back to reference Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 292:8–16PubMedCrossRef Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 292:8–16PubMedCrossRef
15.
go back to reference Bloomston M, Frankel WL, Petrocca F et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908PubMedCrossRef Bloomston M, Frankel WL, Petrocca F et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908PubMedCrossRef
16.
go back to reference Szafranska AE, Davison TS, John J et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442–4452PubMedCrossRef Szafranska AE, Davison TS, John J et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442–4452PubMedCrossRef
17.
go back to reference Dillhoff M, Liu J, Frankel W et al (2008) MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg 12:2171–2176PubMedCrossRef Dillhoff M, Liu J, Frankel W et al (2008) MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg 12:2171–2176PubMedCrossRef
18.
go back to reference Szafranska AE, Doleshal M, Edmunds HS et al (2008) Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. Clin Chem 54:1716–1724PubMedCrossRef Szafranska AE, Doleshal M, Edmunds HS et al (2008) Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. Clin Chem 54:1716–1724PubMedCrossRef
19.
go back to reference Habbe N, Koorstra JB, Mendell JT et al (2009) miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 8:340–346PubMedCrossRef Habbe N, Koorstra JB, Mendell JT et al (2009) miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 8:340–346PubMedCrossRef
20.
go back to reference Seux M, Iovanna J, Dagorn J-C et al (2009) MicroRNAs in pancreatic ductal adenocarcinoma: new diagnostic and therapeutic clues. Pancreatology 9:66–72PubMedCrossRef Seux M, Iovanna J, Dagorn J-C et al (2009) MicroRNAs in pancreatic ductal adenocarcinoma: new diagnostic and therapeutic clues. Pancreatology 9:66–72PubMedCrossRef
21.
go back to reference Wang J, Chen J, Chang P et al (2009) MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res 2:807–813CrossRef Wang J, Chen J, Chang P et al (2009) MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res 2:807–813CrossRef
23.
go back to reference Greither T, Grochola LF, Udelnow A et al (2010) Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer 126:73–80PubMedCrossRef Greither T, Grochola LF, Udelnow A et al (2010) Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer 126:73–80PubMedCrossRef
24.
go back to reference Hwang JH, Voortman J, Giovannetti E et al (2010) Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 5:e10630PubMedCrossRef Hwang JH, Voortman J, Giovannetti E et al (2010) Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 5:e10630PubMedCrossRef
25.
go back to reference Ikenaga N, Ohuchida K, Mizumoto K et al (2010) MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma. Ann Surg Oncol 17:3120–3128PubMedCrossRef Ikenaga N, Ohuchida K, Mizumoto K et al (2010) MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma. Ann Surg Oncol 17:3120–3128PubMedCrossRef
26.
go back to reference Ali S, Almhanna K, Chen W et al (2011) Differential expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. Am J Transl Res 3:28–47 Ali S, Almhanna K, Chen W et al (2011) Differential expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. Am J Transl Res 3:28–47
27.
go back to reference Kong X, Du Y, Wang G et al (2011) Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci 56:602–609PubMedCrossRef Kong X, Du Y, Wang G et al (2011) Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci 56:602–609PubMedCrossRef
28.
go back to reference Ohuchida K, Mizumoto K, Kayashima T et al (2011) MicroRNA expression as a predictive marker for gemcitabine response after surgical resection of pancreatic cancer. Ann Surg Oncol 18:2381–2387PubMedCrossRef Ohuchida K, Mizumoto K, Kayashima T et al (2011) MicroRNA expression as a predictive marker for gemcitabine response after surgical resection of pancreatic cancer. Ann Surg Oncol 18:2381–2387PubMedCrossRef
29.
go back to reference Schultz NA, Werner J, Willenbrock H et al (2012) MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma. Modern Pathol (in press) Schultz NA, Werner J, Willenbrock H et al (2012) MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma. Modern Pathol (in press)
30.
go back to reference Preis M, Gardner TB, Gordon SR et al (2011) MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma. Clin Cancer Res 17:5812–5821PubMedCrossRef Preis M, Gardner TB, Gordon SR et al (2011) MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma. Clin Cancer Res 17:5812–5821PubMedCrossRef
31.
go back to reference Jamieson NB, Morran DC, Morton JP et al (2012) MicroRNA profiles associated with diagnosis, clinicopathological criteria and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clin Cancer Res 18:534–545PubMedCrossRef Jamieson NB, Morran DC, Morton JP et al (2012) MicroRNA profiles associated with diagnosis, clinicopathological criteria and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clin Cancer Res 18:534–545PubMedCrossRef
32.
go back to reference McShane LM, Altman DG, Sauerbrei W et al (2006) Reporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235PubMedCrossRef McShane LM, Altman DG, Sauerbrei W et al (2006) Reporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235PubMedCrossRef
33.
go back to reference WHO Classification of Tumours (2000) Pathology and Genetics of Tumours of the Digestive System. IARC Press, Lyon WHO Classification of Tumours (2000) Pathology and Genetics of Tumours of the Digestive System. IARC Press, Lyon
34.
go back to reference Mar JC, Kimura Y, Schroder K et al (2009) Data-driven normalization strategies for high-throughput quantitative RT-PCR. BMC Bioinformatics 10:110PubMedCrossRef Mar JC, Kimura Y, Schroder K et al (2009) Data-driven normalization strategies for high-throughput quantitative RT-PCR. BMC Bioinformatics 10:110PubMedCrossRef
35.
go back to reference Bovelstad HM, Nygard S, Storvold HL et al (2007) Predicting survival from microarray data—a comparative study. Bioinformatics 23:2080–2087PubMedCrossRef Bovelstad HM, Nygard S, Storvold HL et al (2007) Predicting survival from microarray data—a comparative study. Bioinformatics 23:2080–2087PubMedCrossRef
36.
go back to reference Tibshirani R (1997) The LASSO method for variable selection in the Cox model. Stat Med 16:385–395PubMedCrossRef Tibshirani R (1997) The LASSO method for variable selection in the Cox model. Stat Med 16:385–395PubMedCrossRef
37.
go back to reference Grambsch P, Therneau T (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81:515–526CrossRef Grambsch P, Therneau T (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81:515–526CrossRef
38.
go back to reference R Development Core Team (2007) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-07-0 R Development Core Team (2007) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-07-0
39.
go back to reference Hanoun N, Delpu Y, Suriawinata AA et al (2010) The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. Clin Chem 56:1107–1118PubMedCrossRef Hanoun N, Delpu Y, Suriawinata AA et al (2010) The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. Clin Chem 56:1107–1118PubMedCrossRef
40.
go back to reference Grutzmann R, Foerder M, Alldinger I et al (2003) Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch 443:508–517PubMedCrossRef Grutzmann R, Foerder M, Alldinger I et al (2003) Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch 443:508–517PubMedCrossRef
41.
go back to reference Buchholz M, Braun M, Heidenblut A et al (2005) Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24:6626–6636PubMedCrossRef Buchholz M, Braun M, Heidenblut A et al (2005) Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24:6626–6636PubMedCrossRef
42.
go back to reference Schultz NA, Roslind A, Christensen IJ et al (2011) Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas. Pancreas 41:759–766 Schultz NA, Roslind A, Christensen IJ et al (2011) Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas. Pancreas 41:759–766
43.
go back to reference Torrisani J, Bournet B, du Rieu MC et al (2009) Let-7 microRNA transfer in pancreatic cancer derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gen Ther 20:831–844CrossRef Torrisani J, Bournet B, du Rieu MC et al (2009) Let-7 microRNA transfer in pancreatic cancer derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gen Ther 20:831–844CrossRef
44.
go back to reference Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647PubMedCrossRef Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647PubMedCrossRef
45.
go back to reference Ragusa M, Majorana A, Statello L et al (2010) Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. Mol Cancer Ther 9:3396–3409PubMedCrossRef Ragusa M, Majorana A, Statello L et al (2010) Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. Mol Cancer Ther 9:3396–3409PubMedCrossRef
46.
go back to reference Ferrone CR, Finkelstein DM, Thayer SP et al (2006) Perioperative CA 19–9 levels can predict stage and survival in patients with respectable pancreatic adenocarcinoma. J Clin Oncol 24:2897–2902PubMedCrossRef Ferrone CR, Finkelstein DM, Thayer SP et al (2006) Perioperative CA 19–9 levels can predict stage and survival in patients with respectable pancreatic adenocarcinoma. J Clin Oncol 24:2897–2902PubMedCrossRef
47.
go back to reference Smith RA, Bosonnet L, Ghaneh P et al (2008) Preoperative CA 19–9 levels and lymph node ratio are independent predictors of survival in patients with resected pancreatic ductal adenocarcinoma. Dig Surg 25:226–232PubMedCrossRef Smith RA, Bosonnet L, Ghaneh P et al (2008) Preoperative CA 19–9 levels and lymph node ratio are independent predictors of survival in patients with resected pancreatic ductal adenocarcinoma. Dig Surg 25:226–232PubMedCrossRef
48.
go back to reference Nikiforova MN, Tseng GC, Steward D et al (2008) MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab 93:1600–1608PubMedCrossRef Nikiforova MN, Tseng GC, Steward D et al (2008) MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab 93:1600–1608PubMedCrossRef
49.
go back to reference Hatakeyama H, Cheng H, Wirth P et al (2010) Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One 5:e12702PubMedCrossRef Hatakeyama H, Cheng H, Wirth P et al (2010) Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One 5:e12702PubMedCrossRef
50.
go back to reference Tsang WP, Ng EK, Ng SS et al (2010) Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis 31:350–358PubMedCrossRef Tsang WP, Ng EK, Ng SS et al (2010) Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis 31:350–358PubMedCrossRef
Metadata
Title
Prognostic MicroRNAs in Cancer Tissue from Patients Operated for Pancreatic Cancer—Five MicroRNAs in a Prognostic Index
Authors
Nicolai A. Schultz
Klaus K. Andersen
Anne Roslind
Hanni Willenbrock
Morten Wøjdemann
Julia S. Johansen
Publication date
01-11-2012
Publisher
Springer-Verlag
Published in
World Journal of Surgery / Issue 11/2012
Print ISSN: 0364-2313
Electronic ISSN: 1432-2323
DOI
https://doi.org/10.1007/s00268-012-1705-y

Other articles of this Issue 11/2012

World Journal of Surgery 11/2012 Go to the issue