Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a 465-kDa catalytic subunit of DNA-PK, a DNA repair apparatus. DNA-PKcs has been reported to be a tumor suppressor, but details of its expression in human cancer are controversial. To determine the protein expression and clinical implications of DNA-PKcs in gastric carcinogenesis and cancer progression, we evaluated its expression status by immunohistochemistry in 122 non-neoplastic gastric mucosa samples, and in 115 gastric adenomas and 564 consecutive gastric cancers. In addition, we evaluated the clinicopathologic characteristics of gastric cancers showing altered DNA-PKcs expression, and performed microsatellite instability (MSI) analysis at BAT-26 and frameshift mutation analysis of DNA-PKcs. DNA-PKcs expression was negative in foveolar epithelium of normal gastric mucosal tissues, but was positive in most Helicobacter pylori-associated gastritis, intestinal metaplasia and gastric adenoma tissues. In gastric cancers, negative expression of DNA-PKcs was found in 114 of the 564 (20.2%) cancers and was significantly associated with intratumoral neutrophils, MSI-high (H) phenotype, tumor progression, and poor patient survival (p<0.05). Frameshift mutations of (A)10 mononucleotide repeats in DNA-PKcs were found in 24.3% of MSI-H gastric cancers and these were associated with negative expression of DNA-PKcs. Although patients with MSI-H gastric cancers were found to have a lower risk of lymph node metastasis, gastric cancers harboring the (A)10 mutation of DNA-PKcs were found to have a higher risk of lymph node metastasis. In conclusion, the expression of DNA-PKcs was found to be altered during gastric carcinogenesis and negative DNA-PKcs expression was associated with gastric cancer progression. The (A)10 frameshift mutation of DNA-PKcs in gastric cancers was a target of defective mismatch repair, and was associated with lymph node metastasis.
Lee
Hye Seung
HS
Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 463-707, Korea.
Choe
Gheeyoung
G
Park
Kyoung Un
KU
Park
Do Joong
DJ
Yang
Han-Kwang
HK
Lee
Byung Lan
BL
Kim
Woo Ho
WH
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D002288:Adenocarcinoma, Mucinous / Q000201:enzymology / Q000235:genetics / Q000821:virology; D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000821:virology; D053843:DNA Mismatch Repair; D051747:DNA-Activated Protein Kinase / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016368:Frameshift Mutation; D005753:Gastric Mucosa / Q000201:enzymology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000821:virology; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D008679:Metaplasia / Q000201:enzymology / Q000235:genetics / Q000821:virology; D053842:Microsatellite Instability; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000821:virology