Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study
Open Access
- 1 August 2014
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 9 (8), e103159
- https://doi.org/10.1371/journal.pone.0103159
Abstract
Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.Keywords
This publication has 47 references indexed in Scilit:
- Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic ValuePLoS Medicine, 2013
- Extending pathways and processes using molecular interaction networks to analyse cancer genome dataBMC Bioinformatics, 2010
- Aberrant DNA Methylation in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair DeficiencyGastroenterology, 2010
- Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon CancerJournal of Clinical Oncology, 2009
- Distinct BRAF (V600E) and KRAS Mutations in High Microsatellite Instability Sporadic Colorectal Cancer in African AmericansClinical Cancer Research, 2009
- Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitisJCI Insight, 2008
- Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Improving gene set analysis of microarray data by SAM-GSBMC Bioinformatics, 2007
- CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerNature Genetics, 2006
- The COSMIC (Catalogue of Somatic Mutations in Cancer) database and websiteBritish Journal of Cancer, 2004