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Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations
Faculty
Medicine
Year:
2005
Type of Publication:
Article
Pages:
1542-1551
Authors:
Abdel-Rahman, WM, Ollikainen, M, Kariola, R, Jarvinen, HJ, Mecklin, JP, Nystrom-Lahti, M, Knuutila, S, Peltomaki, P
DOI:
10.1038/sj.onc.1208387
Journal:
ONCOGENE NATURE PUBLISHING GROUP
Volume:
24
Research Area:
Biochemistry \& Molecular Biology; Oncology; Cell Biology; Genetics \& Heredity
ISSN
ISI:000227218200007
Keywords :
HNPCC, colorectal cancer, mismatch repair, beta-catenin, CGH, p53, KRAS, CDX2, LOH
Abstract:
A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected `hidden' MMR gene defects in 42\% of such families, leaving the remaining 58\% `truly' mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among 31 tumors from MMR gene mutation positive families, 25 (81\%) had active Wnt signaling as indicated by aberrant beta-catenin localization with or without CTNNB1 mutations, compared to only 7/18 tumors from MMR gene mutation negative families (39\%; P = 0.005). CGH studies revealed stable profiles in 9/16 (56\%) of MMR gene mutation negative tumors, which was significantly associated with membranous beta-catenin (P = 0.005). Tumors with membranous beta-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear beta-catenin. Thus, a majority of the MMR gene mutation negative cases exhibited a novel molecular pattern characterized by the paucity of changes in common pathways to colorectal carcinogenesis. This feature distinguishes the MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases, suggesting the involvement of novel predisposition genes and pathways in such families.
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