title: Frameshift mutation of WISP3 gene and its regional heterogeneity in gastric and colorectal cancers.
abstract: WISP3 is involved in many cancer-related processes including epithelial-mesenchymal transition, cell death, invasion, and metastasis and is considered a tumor suppressor. The aim of our study was to find whether WISP3 gene was mutated and expressionally altered in gastric (GC) and colorectal cancers (CRCs). WISP3 gene possesses a mononucleotide repeat in the coding sequence that could be mutated in cancers with high microsatellite instability (MSI-H). We analyzed 79 GCs and 156 CRCs, and found that GCs (8.8%) and CRCs (10.5%) with MSI-H, but not those with microsatellite stable/low MSI, harbored a frameshift mutation. We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the WISP3 mutation exhibited regional ITH in 25% of the CRCs. In immunohistochemistry, loss of WISP3 expression was identified in 24% of GCs and 21% of CRCs. The loss of expression was more common in those with WISP3 mutation than with wild-type WISP3 and those with MSI-H than with microsatellite stable/low MSI. Our data indicate that WISP3 harbored not only frameshift mutation but also mutational ITH and loss of expression, which together might play a role in tumorigenesis of GC and CRC with MSI-H by inhibiting tumor suppressor functions of WISP3. Our data also suggest that mutation analysis in multiregions is needed for a proper evaluation of mutation status in GC and CRC with MSI-H.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Ju Hwa
authors.initials: JH
authors.lastname: Lee
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: Eun Mi
authors.initials: EM
authors.lastname: Je
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Ho Shik
authors.initials: HS
authors.lastname: Kim
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: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D055511:CCN Intercellular Signaling Proteins / Q000032:analysis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D009367:Neoplasm Staging; D010641:Phenotype; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human
keywords: Colon cancer; Gastric cancer; Heterogeneity; Somatic mutation; WISP3