Novel Germline and Somatic Mutations of the MSH2 Gene in Hereditary Nonpolyposis Colorectal Cancer. D.C. Ding^1,2, R.L. Huang³, T.Y. Chu¹, K.S. Hwang³. 1) Dept of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C; 2) Graduate Institute of Medical Science, Tzu Chi University, Haulien, Taiwan, R.O.C; 3) Dept of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
   The non-epigenetic somatic second hits of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) were not experimentally characterized before. We describe a HNPCC family in which the proband was found with synchronous cancers of endometrium, ureter, and bladder. A novel germline IVS 12 -2A>G splice acceptor site mutation of the MSH2 gene, 4 bases downstream to the known IVS12 -6T>C polymorphism site, was identified. The allelic specific second hits in different primary tumors were analyzed. In an in-situ transitional cell carcinoma, the wild type allele was lost by loss of heterozygosity (LOH), leaving a transcript skipping the exon 13. In the invasive endometrial carcinoma, LOH of the germline mutant allele occurred. This allowed the discovery of a somatic c.1637 delT mutation at exon 10 of the wild type allele. Replication error phenotype was evident in both of these two tumors. The novel splice acceptor site mutation underscores the importance of the canonical sequences around the splice acceptor site in RNA splicing. To our knowledge, this is the first discovery of a non-deletion somatic mutation of the wild type allele of the mismatch repair gene in HNPCC tumor.