The role of the DNA damage checkpoint pathway in intraductal papillary mucinous neoplasms of the pancreas.
OBJECTIVE
Intraductal papillary mucinous neoplasms (IPMN) are known to show a transition from adenoma to carcinoma accompanied by several molecular abnormalities. ATM-Chk2-p53 DNA damage checkpoint activation, which is involved in prevention of the progression of several tumors, was analyzed to evaluate the role of the DNA damage checkpoint in the progression of IPMNs.


METHODS
One hundred and twenty-eight IPMNs were classified into four groups (intraductal papillary mucinous adenoma, borderline IPMN, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma) and stained immunohistochemically using antibody for Thr(68)-phosphorylated Chk2. Expression of ATM, Chk2, and p21(WAF1) and accumulation of p53 were also analyzed.


RESULTS
Chk2 phosphorylation was shown in all adenomas and showed a significant decreasing trend with the progression of atypia (P < 0.0001 by the Cochran-Armitage test for trend). Expression of p21(WAF1) also exhibited a decreasing tendency (P < 0.0001), reflecting DNA damage checkpoint inactivation. p53 accumulation was mostly detected in malignant IPMNs. It was suggested that the DNA damage checkpoint provides a selective pressure for p53 mutation.


CONCLUSIONS
Our findings indicate that DNA damage checkpoint activation occurs in the early stage of IPMNs and prevents their progression. It is suggested that disturbance of the DNA damage checkpoint pathway due to Chk2 inactivation or p53 mutation contributes to the carcinogenesis of IPMNs.
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Kyushu University Hospital, Fukuoka, Japan.
Yoshihiro
Y
Miyasaka
Eishi
E
Nagai
Hiroshi
H
Yamaguchi
Kei
K
Fujii
Takahiro
T
Inoue
Kenoki
K
Ohuchida
Tomomi
T
Yamada
Kazuhiro
K
Mizumoto
Masao
M
Tanaka
Masazumi
M
Tsuneyoshi
D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D000231:Adenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D064447:Checkpoint Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases