title: Frequent frameshift mutations in 2 mononucleotide repeats of RNF43 gene and its regional heterogeneity in gastric and colorectal cancers.
abstract: RNF43, an E3 ligase, inhibits Wnt signaling by removing Wnt receptors and behaves as a candidate tumor suppressor. Recent studies identified that RNF43 gene was frequently mutated in gastric (GC), colorectal (CRC), and endometrial cancers with high microsatellite instability (MSI-H). The aim of this study is to explore whether RNF43 gene is mutated in GC and CRC in Korean patients and whether the mutations show regional intratumoral heterogeneity (ITH). We analyzed 2 exonic repeats (C6 and G7) of RNF43 in 78 GCs and 130 CRCs by single-strand conformation polymorphism and DNA sequencing analyses. Also, we analyzed regional ITH of RNF43 mutation in 16 CRCs. We found RNF43 frameshift mutation in MSI-H (50/118), the incidence of which was significantly higher than that in microsatellite stable/low microsatellite instability (1/90). GCs showed a significantly higher incidence of the mutation than CRCs (66.7% of GC and 32.9% of CRC with MSI-H). Also, we found that all of the 7 CRCs with the mutations harbored mutational ITH. By immunohistochemistry, we observed that loss of RNF43 expression was significantly more common in those with RNF43 frameshift mutation than those with wild-type RNF43. Our data indicate that RNF43 gene harbored not only exceedingly high mutations but also mutational ITH, which together might play a role in tumorigenesis of GC and CRC. We suggest that regional analysis is required for a more comprehensive evaluation of the mutation status in these tumors.
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Yun Sol
authors: YS
authors: Jo
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Min Sung
authors: MS
authors: Kim
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Ju Hwa
authors: JH
authors: Lee
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Sug Hyung
authors: SH
authors: Lee
authors: Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: achcolo@catholic.ac.kr.
authors: Chang Hyeok
authors: CH
authors: An
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: goldfish@catholic.ac.kr.
authors: Nam Jin
authors: NJ
authors: Yoo
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Cancer; Colorectal cancer; Gastric cancer; Intratumoral heterogeneity; Microsatellite instability; RNF43 mutation