Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer

Alexander Facista, Huy Nguyen, Cristy Lewis, Anil P Rama Rao, Lois Ramsey, Beryl Zaitlin, Valentine N Nfonsam, Robert S Krouse, Harris Bernstein, Claire M. Payne, Stephen Stern, Nicole Oatman, Bhaskar Banerjee, Carol Bernstein

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Cancers often arise within an area of cells (e.g. an epithelial patch) that is predisposed to the development of cancer, i.e. a "field of cancerization" or "field defect." Sporadic colon cancer is characterized by an elevated mutation rate and genomic instability. If a field defect were deficient in DNA repair, DNA damages would tend to escape repair and give rise to carcinogenic mutations.Purpose: To determine whether reduced expression of DNA repair proteins Pms2, Ercc1 and Xpf (pairing partner of Ercc1) are early steps in progression to colon cancer.Results: Tissue biopsies were taken during colonoscopies of 77 patients at 4 different risk levels for colon cancer, including 19 patients who had never had colonic neoplasia (who served as controls). In addition, 158 tissue samples were taken from tissues near or within colon cancers removed by resection and 16 tissue samples were taken near tubulovillous adenomas (TVAs) removed by resection. 568 triplicate tissue sections (a total of 1,704 tissue sections) from these tissue samples were evaluated by immunohistochemistry for 4 DNA repair proteins. Substantially reduced protein expression of Pms2, Ercc1 and Xpf occurred in field defects of up to 10 cm longitudinally distant from colon cancers or TVAs and within colon cancers. Expression of another DNA repair protein, Ku86, was infrequently reduced in these areas. When Pms2, Ercc1 or Xpf were reduced in protein expression, then either one or both of the other two proteins most often had reduced protein expression as well. The mean inner colon circumferences, from 32 resections, of the ascending, transverse and descending/sigmoid areas were measured as 6.6 cm, 5.8 cm and 6.3 cm, respectively. When combined with other measurements in the literature, this indicates the approximate mean number of colonic crypts in humans is 10 million.Conclusions: The substantial deficiencies in protein expression of DNA repair proteins Pms2, Ercc1 and Xpf in about 1 million crypts near cancers and TVAs suggests that the tumors arose in field defects that were deficient in DNA repair and that deficiencies in Pms2, Ercc1 and Xpf are early steps, often occurring together, in progression to colon cancer.

Original languageEnglish (US)
Article number3
JournalGenome Integrity
Volume3
DOIs
StatePublished - Apr 11 2012

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DNA Repair-Deficiency Disorders
DNA Repair Enzymes
Colonic Neoplasms
DNA Repair
Proteins
Adenoma
Neoplasms
Protein Deficiency
Genomic Instability
Sigmoid Colon
Mutation Rate
Colonoscopy
DNA Damage
Colon
Epithelial Cells
Immunohistochemistry
Biopsy
Mutation

Keywords

  • Cancerization
  • Colon cancer
  • DNA repair
  • Ercc1
  • Field defect
  • Genomic instability
  • Ku86
  • Mutation
  • Pms2
  • Xpf

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology

Cite this

Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. / Facista, Alexander; Nguyen, Huy; Lewis, Cristy; Rama Rao, Anil P; Ramsey, Lois; Zaitlin, Beryl; Nfonsam, Valentine N; Krouse, Robert S; Bernstein, Harris; Payne, Claire M.; Stern, Stephen; Oatman, Nicole; Banerjee, Bhaskar; Bernstein, Carol.

In: Genome Integrity, Vol. 3, 3, 11.04.2012.

Research output: Contribution to journalArticle

Facista, A, Nguyen, H, Lewis, C, Rama Rao, AP, Ramsey, L, Zaitlin, B, Nfonsam, VN, Krouse, RS, Bernstein, H, Payne, CM, Stern, S, Oatman, N, Banerjee, B & Bernstein, C 2012, 'Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer', Genome Integrity, vol. 3, 3. https://doi.org/10.1186/2041-9414-3-3
Facista, Alexander ; Nguyen, Huy ; Lewis, Cristy ; Rama Rao, Anil P ; Ramsey, Lois ; Zaitlin, Beryl ; Nfonsam, Valentine N ; Krouse, Robert S ; Bernstein, Harris ; Payne, Claire M. ; Stern, Stephen ; Oatman, Nicole ; Banerjee, Bhaskar ; Bernstein, Carol. / Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. In: Genome Integrity. 2012 ; Vol. 3.
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AU - Facista, Alexander

AU - Nguyen, Huy

AU - Lewis, Cristy

AU - Rama Rao, Anil P

AU - Ramsey, Lois

AU - Zaitlin, Beryl

AU - Nfonsam, Valentine N

AU - Krouse, Robert S

AU - Bernstein, Harris

AU - Payne, Claire M.

AU - Stern, Stephen

AU - Oatman, Nicole

AU - Banerjee, Bhaskar

AU - Bernstein, Carol

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N2 - Background: Cancers often arise within an area of cells (e.g. an epithelial patch) that is predisposed to the development of cancer, i.e. a "field of cancerization" or "field defect." Sporadic colon cancer is characterized by an elevated mutation rate and genomic instability. If a field defect were deficient in DNA repair, DNA damages would tend to escape repair and give rise to carcinogenic mutations.Purpose: To determine whether reduced expression of DNA repair proteins Pms2, Ercc1 and Xpf (pairing partner of Ercc1) are early steps in progression to colon cancer.Results: Tissue biopsies were taken during colonoscopies of 77 patients at 4 different risk levels for colon cancer, including 19 patients who had never had colonic neoplasia (who served as controls). In addition, 158 tissue samples were taken from tissues near or within colon cancers removed by resection and 16 tissue samples were taken near tubulovillous adenomas (TVAs) removed by resection. 568 triplicate tissue sections (a total of 1,704 tissue sections) from these tissue samples were evaluated by immunohistochemistry for 4 DNA repair proteins. Substantially reduced protein expression of Pms2, Ercc1 and Xpf occurred in field defects of up to 10 cm longitudinally distant from colon cancers or TVAs and within colon cancers. Expression of another DNA repair protein, Ku86, was infrequently reduced in these areas. When Pms2, Ercc1 or Xpf were reduced in protein expression, then either one or both of the other two proteins most often had reduced protein expression as well. The mean inner colon circumferences, from 32 resections, of the ascending, transverse and descending/sigmoid areas were measured as 6.6 cm, 5.8 cm and 6.3 cm, respectively. When combined with other measurements in the literature, this indicates the approximate mean number of colonic crypts in humans is 10 million.Conclusions: The substantial deficiencies in protein expression of DNA repair proteins Pms2, Ercc1 and Xpf in about 1 million crypts near cancers and TVAs suggests that the tumors arose in field defects that were deficient in DNA repair and that deficiencies in Pms2, Ercc1 and Xpf are early steps, often occurring together, in progression to colon cancer.

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KW - DNA repair

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KW - Field defect

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KW - Ku86

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KW - Xpf

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