Hereditary cancers - prophylactics diagnosis treatment National Conference of Polish Genetics Cancer Outpatient Clinics. Szczecin 8-9.12.2005

摘要

class="head no_bottom_margin" id="__sec2title">[1] Genetic Dissection of Familial Colorectal CancerPeltomäki P.Department of Medical Genetics, University of Helsinki, FinlandAmong families with clinical presentation of hereditary nonpolyposis colorectal cancer, 30-70% show no germline DNA mismatch repair (MMR) gene mutations. We previously detected 'hidden' MMR gene defects in 42% of such families, leaving the remaining 58% 'truly' mutation negative. Families with no demonstrable germline mutations in MMR genes differ from mutation-positive families in several essential respects, including later age at onset, generally more distal tumour location, and less frequent occurrence of extracolonic cancers (Renkonen et al. 2003), suggesting a different genetic basis for the latter families.To obtain clues to the nature of cancer susceptibility in families with no MMR gene mutations, tumours from such families were investigated. These were found to display a unique molecular and clinicopathological profile characterized by a lack of genomic instability (MIN or CIN), normal (membranous) β-catenin, and low frequency of TP53 mutations (Abdel-Rahman et al. 2005). These features distinguish MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases and should facilitate the identification of novel predisposition genes and pathways in such families.As an alternative and complementary approach, genetic linkage analysis may be used to identify new cancer predisposition genes. Previous linkage and other studies suggest that as yet unidentified, highly or moderately penetrant colorectal cancer susceptibility genes are likely to exist. A collaborative effort for the identification of novel susceptibility genes in Polish families will be discussed.References1. Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, Aittomäki K, Järvinen HJ, Mecklin J-P, Lindblom A and Peltomäki P. Altered expression of MLH1, MSH2 and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol 2003; 21: 3629-3637.2. Abdel-Rahman WM, Ollikainen M, Kariola R, Järvinen HJ, Mecklin J-P, Nyström-Lahti M, Knuutila S and Peltomäki P. Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. Oncogene 2005; 24: 1542-1551.