Identification of a Japanese Lynch syndrome patient with large deletion in the 3′ region of the EPCAM gene

abstract

Germline deletion of the 3′ portion of the Epithelial Cell Adhesion Molecule (EPCAM) gene located 5′ upstream of MutS Homolog 2 (MSH2) is a novel mechanism for its inactivation in Lynch syndrome. However, its contribution in Japanese Lynch syndrome patients is poorly understood. Moreover, somatic events inactivating the remaining allele of MSH2 in cancer tissue have not been elucidated in Lynch syndrome patients with such EPCAM deletions. We identified a Japanese Lynch syndrome patient with colon cancer who evidenced germline deletion of a 4130 bp fragment of EPCAM encompassing exons 8 and 9 (c.859-672_*2170del). In normal colonic mucosa, two known fusion-transcripts of EPCAM/MSH2 generated from the rearranged gene were observed and heterozygous methylation of the MSH2 gene promoter was detected. In cancer tissue, dense methylation of MSH2 was observed and MLPA analysis demonstrated somatic deletion of the remaining EPCAM allele including exon 9, indicating that somatic deletion of EPCAM is responsible for complete inactivation of MSH2.