Abstract 4572: Frequent MLL3 frameshift mutations in microsatellite-deficient colorectal cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 4572
• Main Authors: Watanabe, Yoshiyuki, Castoro, Ryan J., Kim, Hyun Soo, Kleb, Brittany, Oikawa, Ritsuko, Hiraishi, Tetsuya, Ahmed, Saira S., Chung, Woonbok, Cho, Mee-Yon, Toyota, Minoru, Itoh, Fumio, Estecio, Marcos R. H., Shen, Lanlan, Jelinek, Jaroslav, Issa, Jean-Pierre J.
• Format: Journal Article
• Language: English; Japanese
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-4572

Background: MLL3 is a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study. Methods & Results: We analyzed mutations of the coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cell lines and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31%) both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, R=0.88, p<0.001) and frequent hypermethylation (83%) in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 locus was unmethylated. Conclusions: We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown that the CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cell lines but also primary tumors and normal colon, and this region is highly homologous to a pseudogene (psiTPTE22) that shows age-related DNA methylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4572. doi:1538-7445.AM2012-4572