Discovery and Validation of Molecular Biomarkers for Colorectal Adenomas and Cancer with Application to Blood Testing

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Jan 26

PMID 22276102

Citations 21

Authors

Lawrence C LaPointe

Susanne K Pedersen

Robert Dunne

Glenn S Brown

Letitia Pimlott

Snigdha Gaur

Aidan McEvoy

Melissa Thomas

David Wattchow

Peter L Molloy

Graeme P Young

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Colorectal cancer incidence and deaths are reduced by the detection and removal of early-stage, treatable neoplasia but we lack proven biomarkers sensitive for both cancer and pre-invasive adenomas. The aims of this study were to determine if adenomas and cancers exhibit characteristic patterns of biomarker expression and to explore whether a tissue-discovered (and validated) biomarker is differentially expressed in the plasma of patients with colorectal adenomas or cancer.

Methods: Candidate RNA biomarkers were identified by oligonucleotide microarray analysis of colorectal specimens (222 normal, 29 adenoma, 161 adenocarcinoma and 50 colitis) and validated in a previously untested cohort of 68 colorectal specimens using a custom-designed oligonucleotide microarray. One validated biomarker, KIAA1199, was assayed using qRT-PCR on plasma extracted RNA from 20 colonoscopy-confirmed healthy controls, 20 patients with adenoma, and 20 with cancer.

Results: Genome-wide analysis uncovered reproducible gene expression signatures for both adenomas and cancers compared to controls. 386/489 (79%) of the adenoma and 439/529 (83%) of the adenocarcinoma biomarkers were validated in independent tissues. We also identified genes differentially expressed in adenomas compared to cancer. KIAA1199 was selected for further analysis based on consistent up-regulation in neoplasia, previous studies and its interest as an uncharacterized gene. Plasma KIAA1199 RNA levels were significantly higher in patients with either cancer or adenoma (31/40) compared to neoplasia-free controls (6/20).

Conclusions: Colorectal neoplasia exhibits characteristic patterns of gene expression. KIAA1199 is differentially expressed in neoplastic tissues and KIAA1199 transcripts are more abundant in the plasma of patients with either cancer or adenoma compared to controls.

Citing Articles

The crucial role of CEMIP in cancer metastasis: Mechanistic insights and clinical implications.

Ko Y, Jo J, Song S, Lee H FASEB J. 2025; 39(1):e70284.

PMID: 39758005 PMC: 11701794. DOI: 10.1096/fj.202402522R.

Plasma Circulating mRNA Profile for the Non-Invasive Diagnosis of Colorectal Cancer Using NanoString Technologies.

Tsang H, Pei X, Wong Y, Wong S Int J Mol Sci. 2024; 25(5).

PMID: 38474258 PMC: 10932272. DOI: 10.3390/ijms25053012.

Thresholding Gini variable importance with a single-trained random forest: An empirical Bayes approach.

Dunne R, Reguant R, Ramarao-Milne P, Szul P, Sng L, Lundberg M Comput Struct Biotechnol J. 2023; 21:4354-4360.

PMID: 37711185 PMC: 10497997. DOI: 10.1016/j.csbj.2023.08.033.

CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer.

Domanegg K, Sleeman J, Schmaus A Cancers (Basel). 2022; 14(20).

PMID: 36291875 PMC: 9600181. DOI: 10.3390/cancers14205093.

Integration of the Microbiome, Metabolome and Transcriptomics Data Identified Novel Metabolic Pathway Regulation in Colorectal Cancer.

Bisht V, Nash K, Xu Y, Agarwal P, Bosch S, Gkoutos G Int J Mol Sci. 2021; 22(11).

PMID: 34071236 PMC: 8198673. DOI: 10.3390/ijms22115763.

References

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

Bland J, Altman D . Comparing methods of measurement: why plotting difference against standard method is misleading. Lancet. 1995; 346(8982):1085-7. DOI: 10.1016/s0140-6736(95)91748-9. View

Bland J, Altman D . Multiple significance tests: the Bonferroni method. BMJ. 1995; 310(6973):170. PMC: 2548561. DOI: 10.1136/bmj.310.6973.170. View

Park D, Ryu S, Kim Y, Lee S, Lee C, Eun C . Comparison of guaiac-based and quantitative immunochemical fecal occult blood testing in a population at average risk undergoing colorectal cancer screening. Am J Gastroenterol. 2010; 105(9):2017-25. DOI: 10.1038/ajg.2010.179. View

Nannini M, Pantaleo M, Maleddu A, Astolfi A, Formica S, Biasco G . Gene expression profiling in colorectal cancer using microarray technologies: results and perspectives. Cancer Treat Rev. 2008; 35(3):201-9. DOI: 10.1016/j.ctrv.2008.10.006. View

Cunningham D, Atkin W, Lenz H, Lynch H, Minsky B, Nordlinger B . Colorectal cancer. Lancet. 2010; 375(9719):1030-47. DOI: 10.1016/S0140-6736(10)60353-4. View

Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M . Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann Surg Oncol. 2009; 16(7):2042-51. DOI: 10.1245/s10434-009-0469-6. View

Atkin W, Edwards R, Kralj-Hans I, Wooldrage K, Hart A, Northover J . Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. 2010; 375(9726):1624-33. DOI: 10.1016/S0140-6736(10)60551-X. View

Michishita E, Garces G, Barrett J, Horikawa I . Upregulation of the KIAA1199 gene is associated with cellular mortality. Cancer Lett. 2005; 239(1):71-7. DOI: 10.1016/j.canlet.2005.07.028. View

10.

Pradervand S, Paillusson A, Thomas J, Weber J, Wirapati P, Hagenbuchle O . Affymetrix Whole-Transcript Human Gene 1.0 ST array is highly concordant with standard 3' expression arrays. Biotechniques. 2008; 44(6):759-62. DOI: 10.2144/000112751. View

11.

Lane J, Chow E, Young G, Good N, Smith A, Bull J . Interval fecal immunochemical testing in a colonoscopic surveillance program speeds detection of colorectal neoplasia. Gastroenterology. 2010; 139(6):1918-26. DOI: 10.1053/j.gastro.2010.08.005. View

12.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

13.

Galamb O, Spisak S, Sipos F, Toth K, Solymosi N, Wichmann B . Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor. Br J Cancer. 2010; 102(4):765-73. PMC: 2837560. DOI: 10.1038/sj.bjc.6605515. View

14.

LaPointe L, Dunne R, Brown G, Worthley D, Molloy P, Wattchow D . Map of differential transcript expression in the normal human large intestine. Physiol Genomics. 2007; 33(1):50-64. DOI: 10.1152/physiolgenomics.00185.2006. View

15.

Chan S, Griffith O, Tai I, Jones S . Meta-analysis of colorectal cancer gene expression profiling studies identifies consistently reported candidate biomarkers. Cancer Epidemiol Biomarkers Prev. 2008; 17(3):543-52. DOI: 10.1158/1055-9965.EPI-07-2615. View

16.

Levin B, Lieberman D, McFarland B, Andrews K, Brooks D, Bond J . Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008; 134(5):1570-95. DOI: 10.1053/j.gastro.2008.02.002. View

17.

Simon R, Radmacher M, Dobbin K, McShane L . Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. J Natl Cancer Inst. 2003; 95(1):14-8. DOI: 10.1093/jnci/95.1.14. View

18.

Young G, Cole S . Which fecal occult blood test is best to screen for colorectal cancer?. Nat Clin Pract Gastroenterol Hepatol. 2009; 6(3):140-1. DOI: 10.1038/ncpgasthep1358. View

19.

Irizarry R, Hobbs B, Collin F, Beazer-Barclay Y, Antonellis K, Scherf U . Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-64. DOI: 10.1093/biostatistics/4.2.249. View

20.

Donia D, Divizia M, Pana A . Use of armored RNA as a standard to construct a calibration curve for real-time RT-PCR. J Virol Methods. 2005; 126(1-2):157-63. DOI: 10.1016/j.jviromet.2005.02.004. View