TY - JOUR
T1 - Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers
AU - Cappellesso, Rocco
AU - Lo Mele, Marcello
AU - Munari, Giada
AU - Rosa-Rizzotto, Erik
AU - Guido, Ennio
AU - De Lazzari, Franca
AU - Pilati, Pierluigi
AU - Tonello, Marco
AU - Farinati, Fabio
AU - Realdon, Stefano
AU - Fassan, Matteo
AU - Rugge, Massimo
N1 - Copyright © 2019 Elsevier GmbH. All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Adenocarcinoma/genetics
KW - Adenoma/genetics
KW - Aged
KW - Colonic Polyps/pathology
KW - Colorectal Neoplasms/genetics
KW - Disease Progression
KW - Female
KW - Humans
KW - Male
KW - Middle Aged
KW - Precancerous Conditions/genetics
U2 - 10.1016/j.prp.2019.02.001
DO - 10.1016/j.prp.2019.02.001
M3 - Article
C2 - 30738693
VL - 215
SP - 957
EP - 962
JO - Pathology Research and Practice
JF - Pathology Research and Practice
SN - 0344-0338
IS - 5
ER -