Tu1682 Defective DNA Mismatch Repair Activity Is Common in Sporadic Sebaceous Neoplasms, and an Ineffective Approach to Screen for Lynch Syndrome

Abstract

(Background) We have demonstrated that down-regulation of hMSH3 results in low levels of microsatellite instability (MSI-L) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in tissue cultured cell lines. Primary tumor tissues exhibiting MSIL and/or EMAST from stage II/III CRC show intra-tumor depression of hMSH3 and upregulation of GLUT1 that is a marker for hypoxia. In vitro, hypoxia induces down-regulation of hMSH3 and the development of EMAST in CRC cell lines. Finally, Stage II/III primary CRC exhibitingMSI-L/EMAST has a shorter recurrence-free survival than that of microsatellite stable counterparts not exhibiting MSI-L/EMAST. These results support the concept that intra-tumor hypoxia may induce MSI-L/EMAST through down-regulation of hMSH3 and enhance the aggressiveness of primary CRC, leading to recurrence and/or distant metastasis. Thus, MSI-L/EMAST could be a marker for identifying genetic and/or epigenetic changes that control recurrence and/or distant metastasis from primary CRC. We previously reported that LOH at the SMARCA2 locus on 9p24.3 is significantly high in liver metastasis (LM) exhibiting MSI-L/EMAST (termed moderate MSI: MSI-M) from primary CRC. (Aim) The purpose of this study is to determine the pathobiological significance of MSI-L/EMAST and LOH at SMARCA2 region in CRC. (Methods) Eighty three LMs and 186 primary CRC with known clinicopathological factors and disease outcome were analyzed for MSI/EMAST and LOH at the 9p24.2 region. Significant associations between factors were determined by various statistical analyses. (Results) We proposed that a locus affected by 9p24.2 LOH might promote metastasis from primary CRC; such a locus was mapped to an 80 kb region at the 3' boundary of the SMARCA2 gene. Stage II and III primary CRCs exhibiting MSIM and 9p24.2 LOH were significantly more likely to give rise to a solitary LM suitable for hepatectomy, whereas MSI-M-positive counterparts without 9p24.2 LOH, or highly microsatellite stable (HMSS) tissues were more likely to give rise to simultaneous metastases to multiple organs, and therefore, not suitable for surgical management. Multivariate analysis showed that MSI-M with 9p24.2 LOH in the primary CRC is an independent positive prognostic factor following recurrence (HR = .1981, P=.0007). (Conclusions) The presence or absence of 9p24.2 LOH in Stage II/III primary CRCwithMSI-M is an important determinant of the aggressiveness of the recurrent metastasis.