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 β-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 β-catenin (P=0.005). Tumors with membranous β-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear β-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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Acknowledgements
We thank Saila Saarinen for expert technical assistance and Katja Kuosa for help with sample collection. This work was supported by the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cancer Foundation, the Finnish Cultural Foundation, the Paulo Foundation and the Helsinki University Central Hospital.
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Abdel-Rahman, W., Ollikainen, M., Kariola, R. et al. Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. Oncogene 24, 1542–1551 (2005). https://doi.org/10.1038/sj.onc.1208387
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DOI: https://doi.org/10.1038/sj.onc.1208387
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