Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer.

Huy Nguyen, Cristy Loustaunau, Alexander Facista, Lois Ramsey, Nadia Hassounah, Hilary Taylor, Robert Krouse, Claire M. Payne, V. Liana Tsikitis, Steve Goldschmid, Bhaskar Banerjee, Rafael F. Perini, Carol Bernstein

Research output: Contribution to journalArticle

Abstract

In carcinogenesis, the "field defect" is recognized clinically because of the high propensity of survivors of certain cancers to develop other malignancies of the same tissue type, often in a nearby location. Such field defects have been indicated in colon cancer. The molecular abnormalities that are responsible for a field defect in the colon should be detectable at high frequency in the histologically normal tissue surrounding a colonic adenocarcinoma or surrounding an adenoma with advanced neoplasia (well on the way to a colon cancer), but at low frequency in the colonic mucosa from patients without colonic neoplasia. Using immunohistochemistry, entire crypts within 10 cm on each side of colonic adenocarcinomas or advanced colonic neoplasias were found to be frequently reduced or absent in expression for two DNA repair proteins, Pms2 and/or ERCC1. Pms2 is a dual role protein, active in DNA mismatch repair as well as needed in apoptosis of cells with excess DNA damage. ERCC1 is active in DNA nucleotide excision repair. The reduced or absent expression of both ERCC1 and Pms2 would create cells with both increased ability to survive (apoptosis resistance) and increased level of mutability. The reduced or absent expression of both ERCC1 and Pms2 is likely an early step in progression to colon cancer. DNA repair gene Ku86 (active in DNA non-homologous end joining) and Cytochrome c Oxidase Subunit I (involved in apoptosis) had each been reported to be decreased in expression in mucosal areas close to colon cancers. However, immunohistochemical evaluation of their levels of expression showed only low to modest frequencies of crypts to be deficient in their expression in a field defect surrounding colon cancer or surrounding advanced colonic neoplasia. We show, here, our method of evaluation of crypts for expression of ERCC1, Pms2, Ku86 and CcOI. We show that frequency of entire crypts deficient for Pms2 and ERCC1 is often as great as 70% to 95% in 20 cm long areas surrounding a colonic neoplasia, while frequency of crypts deficient in Ku86 has a median value of 2% and frequency of crypts deficient in CcOI has a median value of 16% in these areas. The entire colon is 150 cm long (about 5 feet) and has about 10 million crypts in its mucosal layer. The defect in Pms2 and ERCC1 surrounding a colon cancer thus may include 1 million crypts. It is from a defective crypt that colon cancer arises.

Original languageEnglish (US)
JournalJournal of Visualized Experiments
Issue number41
StatePublished - 2010
Externally publishedYes

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Colonic Neoplasms
DNA
Defects
Repair
Cell death
Neoplasms
DNA Repair
Apoptosis
Colon
Tissue
Adenocarcinoma
DNA End-Joining Repair
Proteins
Electron Transport Complex IV
Nucleotides
DNA Mismatch Repair
Joining
Adenoma
DNA Damage
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nguyen, H., Loustaunau, C., Facista, A., Ramsey, L., Hassounah, N., Taylor, H., ... Bernstein, C. (2010). Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer. Journal of Visualized Experiments, (41).

Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer. / Nguyen, Huy; Loustaunau, Cristy; Facista, Alexander; Ramsey, Lois; Hassounah, Nadia; Taylor, Hilary; Krouse, Robert; Payne, Claire M.; Tsikitis, V. Liana; Goldschmid, Steve; Banerjee, Bhaskar; Perini, Rafael F.; Bernstein, Carol.

In: Journal of Visualized Experiments, No. 41, 2010.

Research output: Contribution to journalArticle

Nguyen, H, Loustaunau, C, Facista, A, Ramsey, L, Hassounah, N, Taylor, H, Krouse, R, Payne, CM, Tsikitis, VL, Goldschmid, S, Banerjee, B, Perini, RF & Bernstein, C 2010, 'Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer.', Journal of Visualized Experiments, no. 41.
Nguyen H, Loustaunau C, Facista A, Ramsey L, Hassounah N, Taylor H et al. Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer. Journal of Visualized Experiments. 2010;(41).
Nguyen, Huy ; Loustaunau, Cristy ; Facista, Alexander ; Ramsey, Lois ; Hassounah, Nadia ; Taylor, Hilary ; Krouse, Robert ; Payne, Claire M. ; Tsikitis, V. Liana ; Goldschmid, Steve ; Banerjee, Bhaskar ; Perini, Rafael F. ; Bernstein, Carol. / Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer. In: Journal of Visualized Experiments. 2010 ; No. 41.
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AU - Hassounah, Nadia

AU - Taylor, Hilary

AU - Krouse, Robert

AU - Payne, Claire M.

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