Alteration of the DNA damage response in colorectal tumor progression

• Published in: Human pathology Vol. 44; no. 6; pp. 1038 - 1046
• Main Authors: Takabayashi, Hiroaki, MD, Wakai, Toshifumi, MD, PhD, Ajioka, Yoichi, MD, PhD, Korita, Pavel V., MD, PhD, Yamaguchi, Naoyuki, BS
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2013; Elsevier Limited
• Subjects: Apoptosis; Cancer; Cancer therapies; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease Progression; DNA Breaks, Double-Stranded; DNA Damage - genetics; DNA damage response; DNA repair; Double-strand breaks; Fluorescent Antibody Technique; Histones - metabolism; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - metabolism; p53-binding protein 1; Pathology; Proteins; Studies; Tumor Suppressor p53-Binding Protein 1; Tumors; University graduates; γH2AX; Japan; p53-binding protein 1; Double-strand breaks; DSB(s); DNA double-strand break(s); DDR; DNA damage response; 53BP1; Colorectal carcinoma; γH2AX; labeling index; LI
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2012.09.006

Summary Recent studies have demonstrated increased levels of DNA double-strand breaks (DSBs) and activation of the DNA damage response (DDR) in precancerous lesions during cancer development. Those observations have not been fully elucidated using paraffin-embedded tissues of colorectal tumors. The aims of this study were to analyze the presence of DSBs and DDR activation mediated by p53-binding protein 1 (53BP1), which is a conserved checkpoint and DNA repair protein, and to clarify their association with colorectal tumor progression. We used immunohistochemical staining to investigate the expression of γ H2AX, a sensitive marker for DSBs, in 152 colorectal tumors (46 low-grade adenomas, 25 high-grade adenomas, 25 intramucosal carcinomas, and 56 invasive carcinomas). The colocalization of γ H2AX and 53BP1, which is strongly associated with the DSB repair process, was analyzed using double-label immunofluorescence. Elevated γ H2AX expression was identified in 16 (16.7%) of 96 intramucosal neoplasias and in 19 (33.9%) of 56 invasive carcinomas. Double-label immunofluorescence occasionally revealed cells, particularly in invasive carcinoma, with γ H2AX foci that did not colocalize with 53BP1. The percentage of tumor cells with γ H2AX foci that colocalized with 53BP1 was significantly lower in invasive carcinoma than in intramucosal neoplasia (median percentage, 54.8% and 88.5%, respectively; P = .001). In conclusion, the number of cells with DSBs increases in intramucosal neoplasia and invasive carcinoma. The decreasing number of cells with colocalization of γ H2AX and 53BP1 during the progression from intramucosal neoplasia to invasive carcinoma suggests that DDR, at least mediated by 53BP1, is inefficient during the process of cancer invasion.