title: Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability.
abstract: Histone methyltransferase (HMT), which catalyzes a histone methylation, is frequently altered in cancers at mutation and expression levels. The aims of this study were to explore whether SETD1B, SETDB2, and SETD2, SET domain-containing HMT genes, are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). In a public database, we found that SETD1B, SETDB2, and SETD2 had mononucleotide repeats in coding sequences that might be mutation targets in cancers with microsatellite instability (MSI). We analyzed the mutations in 76 GCs and 93 CRCs and found SETD1B (38.7% of GC and 35.6% of CRC with high MSI [MSI-H]), SETDB2 (11.1% of CRC with MSI-H), and SETD2 frameshift mutations (6.7% of CRC with MSI-H). These mutations were not found in stable MSI/low MSI. In addition, we analyzed intratumoral heterogeneity (ITH) of SETD1B mutation in 6 CRCs and found that 2 CRCs harbored regional ITH of SETD1B. We also analyzed SETD1B expression in GC and CRC by immunohistochemistry. Loss of SETD1B expression was identified in 15% to 55% of the GC and CRC with respect to the MSI status. Of note, the loss of expression was more common in those with SETD1B mutations than those with wild-type SETD1B. We identified alterations of SET domain-containing HMT at various levels (frameshift mutations, genetic ITH, and expression loss), which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our data suggest that mutation analysis in multiple regions is needed for a better evaluation of mutation status in CRC with MSI-H.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Youn Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Oh
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Mi Ryoung
authors.initials: MR
authors.lastname: Choi
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Gwak
authors.affiliation: Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Yeun Jun
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. Electronic address: suhulee@catholic.ac.kr.
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D016368:Frameshift Mutation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008745:Methylation; D053842:Microsatellite Instability; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Cancer; Heterogeneity; Microsatellite instability; Mutation; SETD1B