title: KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior.
abstract: Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli, perineural invasion, and an infiltrative growth pattern. Mutations in the genes of the Ras-mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase pathways are associated with epithelial-mesenchymal transition and an aggressive CRC phenotype and have been used in patient stratification for anti-epidermal growth factor receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multigene panel, we detected KRAS, NRAS, BRAF, PIK3CA, TP53, and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations (P=.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB (P=.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have lymphovascular tumor emboli and perineural invasion (P=.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival (P=.030), whereas BRAF mutations were associated with extracellular mucin deposition (P=.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea.
authors.forename: Mineui
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Department of Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea.
authors.forename: Byung Chun
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, Republic of Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Shin
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Jihun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Chun
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05535, Republic of Korea.
authors.forename: Tae-Im
authors.initials: TI
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24253, Republic of Korea.
authors.forename: Kyung-Chan
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Computer Engineering, Hallym University, Chuncheon 24253, Republic of Korea.
authors.forename: Young Woong
authors.initials: YW
authors.lastname: Ko
authors.affiliation: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea. Electronic address: jwkim@hallym.or.kr.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D017933:Peripheral Nervous System / Q000473:pathology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; Colorectal carcinoma; KRAS; PIK3CA; Tumor budding