title: Molecular markers of carcinogenesis for risk stratification of individuals with colorectal polyps: a case-control study.
abstract: Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer. We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n = 216; 46% female) in which cases were patients with colorectal cancer and synchronous adenoma and controls were patients with adenoma but no colorectal cancer at baseline or within 5 years of follow-up. In phase I of analyses, we compared expression of molecular markers of carcinogenesis in case and control adenomas, blind to case status. In phase II of analyses, patients were randomly divided into independent training and validation groups to develop a model for predicting case status. We found that seven markers [p53, p21, Cox-2, β-catenin (BCAT), DNA-dependent protein kinase (DNApkcs), survivin, and O6-methylguanine-DNA methyltransferase (MGMT)] were significantly associated with case status on unadjusted analyses, as well as analyses adjusted for age and advanced adenoma status (P < 0.01 for at least one marker component). When applied to the validation set, a predictive model using these seven markers showed substantial accuracy for identifying cases [area under the receiver operation characteristic curve (AUC), 0.83; 95% confidence interval (CI), 0.74-0.92]. A parsimonious model using three markers performed similarly to the seven-marker model (AUC, 0.84). In summary, we found that molecular markers of carcinogenesis distinguished adenomas from patients with and without colorectal cancer. Furthermore, we speculate that prospective studies using molecular markers to identify individuals with polyps at risk for future neoplasia are warranted.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California. Division of Gastroenterology, Department of Internal Medicine, University of California San Diego, La Jolla, California. s1gupta@ucsd.edu.
authors.forename: Samir
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Han
authors.initials: H
authors.lastname: Sun
authors.affiliation: Maricopa Integrated Health System, Emergency Medicine, Phoenix, AZ.
authors.forename: Sang
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Pediatrics, Louisiana State University School of Medicine in New Orleans.
authors.forename: Joy
authors.initials: J
authors.lastname: Storm
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.affiliation: University of Texas School of Public Health, Houston, Texas. Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Bijal A
authors.initials: BA
authors.lastname: Balasubramanian
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Miraca Life Sciences, Irving, Texas.
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.affiliation: Department of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
mesh_terms: D000236:Adenoma / Q000175:diagnosis / Q000378:metabolism; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis; D016022:Case-Control Studies; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007417:Intestinal Polyps; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D019853:O(6)-Methylguanine-DNA Methyltransferase
references.citation: Eur J Cancer. 2005 Feb;41(3):416-22
references.pmid: 15691642
references.citation: Histopathology. 2006 Oct;49(4):411-24
references.pmid: 16978205
references.citation: Cell Oncol. 2007;29(4):301-13
references.pmid: 17641414
references.citation: Anticancer Res. 2007 Nov-Dec;27(6C):4465-71
references.pmid: 18214062
references.citation: J Mol Diagn. 2008 Jan;10(1):13-27
references.pmid: 18165277
references.citation: Cancer. 1953 Sep;6(5):963-8
references.pmid: 13094644
references.citation: CA Cancer J Clin. 2006 May-Jun;56(3):143-59; quiz 184-5
references.pmid: 16737947
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Ann Intern Med. 2008 Mar 18;148(6):419-26
references.pmid: 18347350
references.citation: World J Gastroenterol. 2006 Aug 28;12(32):5148-52
references.pmid: 16937524
references.citation: N Engl J Med. 2007 May 24;356(21):2195-8
references.pmid: 17522404
references.citation: Cell Res. 2008 Jan;18(1):134-47
references.pmid: 18157161
references.citation: Am J Surg Pathol. 2001 Sep;25(9):1204-7
references.pmid: 11688582
references.citation: Eur J Cancer Prev. 2003 Oct;12(5):439-43
references.pmid: 14512812
references.citation: J Cancer. 2013;4(3):251-61
references.pmid: 23459690
references.citation: Cancer Res. 1994 Sep 1;54(17):4798-804
references.pmid: 8062281
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5
references.pmid: 9618505
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Bioinformatics. 2003 Sep 1;19(13):1636-43
references.pmid: 12967959
references.citation: Gastroenterology. 2009 Mar;136(3):832-41
references.pmid: 19171141
references.citation: Cancer Res. 2009 Jul 1;69(13):5269-84
references.pmid: 19491253
references.citation: Int J Colorectal Dis. 2008 Apr;23(4):389-400
references.pmid: 18189140
references.citation: Clin Gastroenterol Hepatol. 2009 Dec;7(12):1272-8
references.pmid: 19523536
references.citation: Am J Med Sci. 2008 Nov;336(5):407-17
references.pmid: 19011398
references.citation: Cancer Prev Res (Phila). 2013 Oct;6(10):1111-9
references.pmid: 23983085
references.citation: Histopathology. 2007 Jan;50(1):113-30
references.pmid: 17204026
references.citation: Mod Pathol. 2015 Jan;28(1):14-29
references.pmid: 24925058
references.citation: Br J Cancer. 2000 May;82(10):1689-93
references.pmid: 10817505
references.citation: Gut. 2010 May;59(5):666-89
references.pmid: 20427401
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1443-50
references.pmid: 16896030
references.citation: Nutr Cancer. 2005;51(2):140-5
references.pmid: 15860435
references.citation: Gastroenterology. 2012 Sep;143(3):844-857
references.pmid: 22763141
references.citation: Gastroenterology. 2007 Jan;132(1):127-38
references.pmid: 17087942
references.citation: J Pathol. 2002 Apr;196(4):386-93
references.pmid: 11920733
references.citation: Appl Immunohistochem Mol Morphol. 2004 Dec;12(4):380-6
references.pmid: 15536342
references.citation: Cancer Res. 2001 Dec 1;61(23):8381-4
references.pmid: 11731412
references.citation: Annu Rev Pathol. 2011;6:479-507
references.pmid: 21090969
references.citation: Histopathology. 2006 Oct;49(4):406-10
references.pmid: 16978204
references.citation: BMC Bioinformatics. 2006 Jan 06;7:3
references.pmid: 16398926
references.citation: Nat Rev Mol Cell Biol. 2004 Sep;5(9):752-62
references.pmid: 15340382
references.citation: Carcinogenesis. 2007 Sep;28(9):1985-90
references.pmid: 17621591
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Sep;14(9):2076-81
references.pmid: 16172212
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Jun;12(6):559-65
references.pmid: 12815003
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1203-9
references.pmid: 15709190
references.citation: Gastrointest Endosc. 2006 Oct;64(4):614-26
references.pmid: 16996358
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2):525-8
references.pmid: 15734982
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):486-93
references.pmid: 16537706
references.citation: Gastroenterology. 2002 Dec;123(6):1770-7
references.pmid: 12454832
references.citation: Gut. 2002 Oct;51 Suppl 5:V6-9
references.pmid: 12221031
references.citation: J Natl Cancer Inst. 2005 Sep 21;97(18):1330-8
references.pmid: 16174854