title: Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.
abstract: Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma.
  
  
  
  A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT).
  
  
  
  The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status.
  
  
  
  SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Envoi Specialist Pathologists, Brisbane, Queensland, Australia.|The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Bettington
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Envoi Specialist Pathologists, Brisbane, Queensland, Australia.
authors.forename: Neal
authors.initials: N
authors.lastname: Walker
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Envoi Specialist Pathologists, Brisbane, Queensland, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Envoi Specialist Pathologists, Brisbane, Queensland, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Brown
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Envoi Specialist Pathologists, Brisbane, Queensland, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clouston
authors.affiliation: The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: McKeone
authors.affiliation: The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Pearson
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leggett
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Whitehall
mesh_terms: D000236:Adenoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003111:Colonic Polyps / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D018899:CpG Islands; D003430:Cross-Sectional Studies; D015254:DNA Modification Methylases / Q000032:analysis / Q000235:genetics; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000032:analysis / Q000235:genetics; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012737:Sex Factors; D047368:Tumor Burden; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics; D060449:Wnt Signaling Pathway; D055815:Young Adult; D051176:beta Catenin / Q000032:analysis / Q000235:genetics
chemical_list: C117307:KRAS protein, human; C501486:MLH1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras); D045643:DNA Repair Enzymes
keywords: COLON CARCINOGENESIS; COLONIC NEOPLASMS; COLONIC POLYPS; COLORECTAL CANCER GENES