title: A clinicopathological and molecular analysis of 200 traditional serrated adenomas.
abstract: The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, β-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; P≤0.0001), were exclusively associated with a precursor polyp (57% versus 0%; P≤0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; P≤0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear β-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wild-type traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma.
authors.affiliation: 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] Envoi Specialist Pathologists, Brisbane, QLD, Australia.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bettington
authors.affiliation: 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Walker
authors.affiliation: 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia [3] Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton, VIC, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: 1] Envoi Specialist Pathologists, Brisbane, QLD, Australia [2] Department of Anatomical Pathology, Pathology Queensland, Brisbane, QLD, Australia.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Brown
authors.affiliation: 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia [3] Department of Anatomical Pathology, Pathology Queensland, Brisbane, QLD, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Diane M
authors.initials: DM
authors.lastname: McKeone
authors.affiliation: The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Pearson
authors.affiliation: Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kerenaftali
authors.initials: K
authors.lastname: Klein
authors.affiliation: 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.affiliation: 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia.
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins