Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers

Rocco Cappellesso, Marcello Lo Mele, Giada Munari, Erik Rosa-Rizzotto, Ennio Guido, Franca De Lazzari, Pierluigi Pilati, Marco Tonello, Fabio Farinati, Stefano Realdon, Matteo Fassan, Massimo Rugge

Research output: Contribution to journalArticlepeer-review

Abstract

Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.

Original languageEnglish
Pages (from-to)957-962
Number of pages6
JournalPathology Research and Practice
Volume215
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • Adenocarcinoma/genetics
  • Adenoma/genetics
  • Aged
  • Colonic Polyps/pathology
  • Colorectal Neoplasms/genetics
  • Disease Progression
  • Female
  • Humans
  • Male
  • Middle Aged
  • Precancerous Conditions/genetics

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