Carcinogenesis Advance Access first published online on June 12, 2008
This version published online on June 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn133
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Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors
Department of Medical Genetics
1 University of Helsinki, Helsinki, Finland; College of Health Sciences
2 University of Sharjah, Sharjah, United Arab Emirates; Department of Pathology
3 Jyväskylä Central Hospital, Jyväskylä, Finland; Second Department of Surgery
4 Helsinki University Hospital, Helsinki, Finland; Department of Surgery
5 Jyväskylä Central Hospital, Jyväskylä, Finland
* Address for correspondence and reprint requests: Prof. Päivi Peltomäki, Department of Medical Genetics, Biomedicum Helsinki, P. O. Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, FINLAND, Phone:+358-9-19125092, FAX: +358-9-19125105, e-mail: Paivi.Peltomaki{at}Helsinki.Fi
Hereditary nonpolyposis colorectal carcinoma (HNPCC/Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nation-wide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (5 bladder and 5 ureter uroepithelial cancers, 4 kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric, and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability (MSI) in tumors varied between high (100 – 96% for ureter, stomach, and colon), intermediate (63 – 60% for endometrium and bladder) and low (25 – 0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) β-catenin was rare and KRAS mutations absent in brain and urological tumors. Compared to other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.
Key Words: Brain tumor • Lynch syndrome/HNPCC • microsatellite instability • promoter methylation • urinary tract tumor
Received January 3, 2008; revised May 21, 2008; accepted May 25, 2008.
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