title: A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix.
abstract: Appendiceal mucinous tumors (AMTs) are classified as low-grade appendiceal mucinous neoplasms (LAMNs) or mucinous adenocarcinomas (MACs), although their carcinogenesis is not well understood. As somatic activating mutations of GNAS are considered to be characteristic of LAMNs while TP53 mutations have been shown to be specific to MACs, MACs are unlikely to result from transformation of LAMNs. However, emerging evidence also shows the presence of GNAS mutations in MACs. We examined 16 AMTs (11 LAMNs and 5 MACs) for genetic alterations of GNAS, KRAS, BRAF, TP53, CTNNB1, and TERT promoter in order to elucidate the possibility of a shared genetic background in the two tumor types. Extensive histological examination revealed the presence of a low-grade component in all cases of MAC. GNAS mutations were detected in two LAMNs and in one MAC, although the GNAS mutation in this MAC was a nonsense mutation (Q227X) expected not to be activating mutation. TP53 mutations were detected in three LAMNs; they were frequently detected in MACs. KRAS mutations were detected in three LAMNs and three MACs, and CTNNB1 mutations were detected in two LAMNs. KRAS mutation and activating mutation of GNAS occurred exclusively in AMTs. BRAF and TERT mutations were not detected. Overexpression of p53 was observed in only two MACs, and p53 immunostaining clearly discriminated the high-grade lesion from a low-grade component in one. These findings suggest that p53 overexpression plays an important role in the carcinogenesis of AMTs and that, in addition to mutations of GNAS, KRAS and TP53 alterations might be shared by AMTs, thus providing evidence for the possible progression of LAMNs to MAC.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Kieko
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan. Electronic address: tysaitou@juntendo.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Alkam
authors.initials: A
authors.lastname: Yimit
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.affiliation: Department of Coloproctological Surgery, Juntendo University School of Medicine, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001063:Appendiceal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010641:Phenotype; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D002864:Chromogranins; C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Appendiceal mucinous neoplasm; GNAS; KRAS; Mismatch repair gene; Mutation; TP53