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Pathol Res Pract. 2019 Feb 3. pii: S0344-0338(18)31599-1. doi: 10.1016/j.prp.2019.02.001. [Epub ahead of print]

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

Author information

1
Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy.
2
Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy; Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy.
3
Gastroenterology Unit, S. Antonio Hospital, Padua, 35128, Italy.
4
Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy.
5
Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy; Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy.
6
Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy.
7
Unit of Digestive Endoscopy, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy.
8
Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy. Electronic address: matteo.fassan@unipd.it.

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.

KEYWORDS:

BRAF; CIMP; Colorectal; Mismatch repair system; Sessile serrated adenoma/polyp

PMID:
30738693
DOI:
10.1016/j.prp.2019.02.001

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