Abstract
Background/purpose
The aim of this study was to clarify the association between the DNA damage response mediated by p53-binding protein 1 (53BP1) in residual carcinoma in situ at ductal stumps and local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma.
Methods
A retrospective analysis was conducted of 11 patients with positive ductal margins with carcinoma in situ. To evaluate the early DNA damage response, the nuclear staining pattern of 53BP1 was examined by immunofluorescence. TUNEL analysis was used to calculate the apoptotic index.
Results
Of the 11 tumor specimens of carcinoma in situ, seven showed diffuse localization of 53BP1 in nuclei (53BP1 inactivation) and four showed discrete nuclear foci of 53BP1 (53BP1 activation); the apoptotic index was significantly decreased in the seven tumor specimens with 53BP1 inactivation compared to the four with 53BP1 activation (median apoptotic index, 1 vs. 22 %; p = 0.003). The cumulative probability of local recurrence was significantly higher in patients with 53BP1 inactivation than in patients with 53BP1 activation (cumulative 5-year local recurrence rate, 60 vs. 0 %; p = 0.019).
Conclusions
Clinically evident local recurrence of residual carcinoma in situ at ductal stumps is closely associated with 53BP1 inactivation and decreased apoptosis.
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References
Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer. 2005;103:1210–6.
Sasaki R, Takeda Y, Funato O, Nitta H, Kawamura H, Uesugi N, et al. Significance of ductal margin status in patients undergoing surgical resection for extrahepatic cholangiocarcinoma. World J Surg. 2007;31:1788–96.
Igami T, Nagino M, Oda K, Nishio H, Ebata T, Yokoyama Y, et al. Clinicopathologic study of cholangiocarcinoma with superficial spread. Ann Surg. 2009;249:296–302.
Ojima H, Kanai Y, Iwasaki M, Hiraoka N, Shimada K, Sano T, et al. Intraductal carcinoma component as a favorable prognostic factor in biliary tract carcinoma. Cancer Sci. 2009;100:62–70.
Shingu Y, Ebata T, Nishio H, Igami T, Shimoyama Y, Nagino M. Clinical value of additional resection of a margin-positive proximal bile duct in hilar cholangiocarcinoma. Surgery. 2010;147:49–56.
Nakanishi Y, Kondo S, Zen Y, Yonemori A, Kubota K, Kawakami H, et al. Impact of residual in situ carcinoma on postoperative survival in 125 patients with extrahepatic bile duct carcinoma. J Hepatobiliary Pancreat Sci. 2010;17:166–73.
Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, et al. γH2AX and cancer. Nat Rev Cancer. 2008;8:957–67.
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907–13.
Difilippantonio S, Gapud E, Wong N, Huang CY, Mahowald G, Chen HT, et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature. 2008;456:529–33.
Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008;26:261–92.
Bartkova J, Horejsí Z, Koed K, Krämer A, Tort F, Zieger K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–70.
Yu T, MacPhail SH, Banáth JP, Klokov D, Olive PL. Endogenous expression of phosphorylated histone H2AX in tumors in relation to DNA double-strand breaks and genomic instability. DNA Repair (Amst). 2006;5:935–46.
Sedelnikova OA, Bonner WM. GammaH2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle. 2006;5:2909–13.
Nuciforo PG, Luise C, Capra M, Pelosi G, d’Adda di Fagagna F. Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression. Carcinogenesis. 2007;28:2082–8.
Schultz LB, Chehab NH, Malikzay A, Halazonetis TD. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol. 2000;151:1381–90.
Rappold I, Iwabuchi K, Date T, Chen J. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J Cell Biol. 2001;153:613–20.
Richardson C, Jasin M. Coupled homologous and nonhomologous repair of a double-strand break preserves genomic integrity in mammalian cells. Mol Cell Biol. 2000;20:9068–75.
Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009;458:591–6.
Ebata T, Watanabe H, Ajioka Y, Oda K, Nimura Y. Pathological appraisal of lines of resection for bile duct carcinoma. Br J Surg. 2002;89:1260–7.
Sakamoto E, Nimura Y, Hayakawa N, Kamiya J, Kondo S, Nagino M, et al. The pattern of infiltration at the proximal border of hilar bile duct carcinoma: a histologic analysis of 62 resected cases. Ann Surg. 1998;227:405–11.
Nimura Y. Staging of biliary carcinoma: cholangiography and cholangioscopy. Endoscopy. 1993;25:76–80.
Risques RA, Lai LA, Brentnall TA, Li L, Feng Z, Gallaher J, et al. Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology. 2008;135:410–8.
Clemons NJ, McColl KE, Fitzgerald RC. Nitric oxide and acid induce double-strand DNA breaks in Barrett’s esophagus carcinogenesis via distinct mechanisms. Gastroenterology. 2007;133:1198–209.
Acknowledgments
The authors would like to thank Professor Kouhei Akazawa, Department of Medical Informatics, Niigata University Medical and Dental Hospital, Niigata, Japan, for suggestions concerning interpretation of statistical analysis in the present manuscript.
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This article is a secondary publication based on a study first reported in the JBA (Journal of Japan Biliary Association) 2010;24:667–674.
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Wakai, T., Shirai, Y., Sakata, J. et al. Early DNA damage response in residual carcinoma in situ at ductal stumps and local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci 20, 362–369 (2013). https://doi.org/10.1007/s00534-012-0539-1
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DOI: https://doi.org/10.1007/s00534-012-0539-1