TGF-α Expression as a Potential Biomarker of Risk Within the Normal-appearing Colorectal Mucosa of Patients with and without Incident Sporadic Adenoma

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To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normalappearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those z55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential ''treatable'' biomarker of risk for colorectal neoplasms.

Section: Participants and Methodsmentioning

confidence: 99%

MutL-Homolog 1 Expression and Risk of Incident, Sporadic Colorectal Adenoma: Search for Prospective Biomarkers of Risk for Colorectal Cancer

Sidelnikov

Bostick

Flanders

et al. 2009

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“…1) and cannot be quantified by eye (e.g., by counting cells). Therefore, MSH2 expression density, detected by immunohistochemical staining, was quantified in the stained slides using image analysis densitometry methods (22,23). The procedure was conducted by one trained "scorer" using a light microscope (Olympus BX40), digital camera (Polaroid DMC Digital Light Microscope Camera), digital drawing tablet, and a customdeveloped plug-in to ImagePro Plus (Media Cybernetics) image analysis software.…”

Section: Participants and Methodsmentioning

confidence: 99%

“…1; refs. 22,23). The software program divided the traced hemicrypt into segments corresponding in width to that of an average normal crypt epithelial cell (6.59 μm; ref.…”

Section: Participants and Methodsmentioning

confidence: 99%

“…The software program divided the traced hemicrypt into segments corresponding in width to that of an average normal crypt epithelial cell (6.59 μm; ref. 21) and then calculated overall hemicrypt-and segment-specific labeling optical density and entered these data into a Microsoft Access database along with various dimensional parameters of the hemicrypt (22,23).…”

Section: Participants and Methodsmentioning

confidence: 99%

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Colorectal Mucosal Expression of MSH2 as a Potential Biomarker of Risk for Colorectal Neoplasms

Sidelnikov

Bostick²,

Flanders³

et al. 2009

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To characterize the expression of the mismatch repair gene MSH2 in normal colorectal crypts in humans and assess parameters of its expression as a potential modifiable biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MSH2 protein, and analyzed using custom quantitative image analysis procedures. MSH2 expression in adenoma cases was lower than in controls by 49% (P = 0.01) and 23% (P = 0.06) in the ascending colon and rectum, respectively, but not in the sigmoid colon. MSH2 expression in the rectum was 39% (P = 0.04) higher in subjects who regularly took a nonsteroidal anti-inflammatory drug than in those who did not, and it tended to be lower in those with adenomas in the right colon and those who had an adenoma with more advanced characteristics. These preliminary data suggest that lower MSH2 expression in the normal colonic mucosa, at least in the ascending colon and rectum, may be associated with increased risk of incident, sporadic colorectal adenoma as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MSH2 expression as a potential modifiable biomarker of risk for colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2965-73)

“…As previously reported (9)(10)(11), the Markers of Adenomatous Polyps II (MAP II) study is a colonoscopy-based case-control study to investigate potentially treatable biomarkers of risk for incident, sporadic colorectal adenomas. Study participants were recruited through the usual scheduling of outpatient elective colonoscopies at Consultants in Gastroenterology, a large private practice gastroenterology group in Columbia, SC.…”

Section: Participant Population and Recruitmentmentioning

confidence: 99%

Markers of the APC/β-Catenin Signaling Pathway as Potential Treatable, Preneoplastic Biomarkers of Risk for Colorectal Neoplasms

Ahearn

Shaukat

Flanders

et al. 2012

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Background: Malfunctioning of the adenomatous polyposis coli (APC)/b-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/b-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma.Methods: We evaluated APC, b-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires.Results: In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total b-catenin expression (APC/b-catenin score) was 14.3% greater in controls than in cases [P ¼ 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, b-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/b-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D 3 concentrations ! 27 ng/mL].Conclusions: These preliminary data suggest that the combined expression of APC and b-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms.Impact: Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 21(6); 969-79. Ó2012 AACR.