title: Mutational and expressional analysis of RFC3, a clamp loader in DNA replication, in gastric and colorectal cancers.
abstract: Parts of gastric (GC) and colorectal cancers (CRC) exhibit microsatellite instability (MSI) that causes frameshift mutations and contributes to cancer development. DNA replication and repair play crucial roles in maintenance of genome stability, and their alterations contribute to cancer development. In this study, we analyzed mutation of RFC1 and RFC3, clamp loaders in DNA replication, in GC and CRC with MSI. We analyzed mononucleotide repeats in RFC1 and RFC3 in 29 GC with high MSI (MSI-H), 20 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 35 CRC with MSI-H, 20 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism. We also analyzed RFC3 expression in the GC and CRC. We found RFC3 frameshift mutations in 7 GC (24.1%) and 9 CRC with MSI-H (25.7%) but not in cancers with MSI-L or MSS. The mutations consisted of 14 c.244delA, one 243_244delAA, and one c.244dupA, which would result in premature stops of RFC3 amino acid synthesis. Loss of RFC3 expression was observed in 51% of the GC and 65% of the CRC, but all of the cancers with RFC3 frameshift mutations were weak or negative. Our data indicate RFC3 mutation and loss of RFC3 expression occur in large fractions of GC and CRC and suggest that these alterations may contribute to the cancer pathogenesis by deregulating DNA repair and replication.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Yoo Ri
authors.initials: YR
authors.lastname: Kim
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Song
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D053842:Microsatellite Instability; D009154:Mutation; D012091:Repetitive Sequences, Nucleic Acid; D051818:Replication Protein C / Q000096:biosynthesis / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: C081632:RFC1 protein, human; C497562:RFC3 protein, human; D051818:Replication Protein C