Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study

PLoS One. 2014 Aug 1;9(8):e103159. doi: 10.1371/journal.pone.0103159. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Cluster Analysis
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Signal Transduction
  • Transcriptome
  • beta Catenin / metabolism

Substances

  • beta Catenin

Associated data

  • GEO/GSE39084

Grant support

This work was supported by a grant from Ligue Régionale Contre le Cancer, Comité du Gers and the program Carte d'Identité des Tumeurs from Ligue Nationale Contre le Cancer. The authors thank the Institut National Contre le Cancer for their support of the clinical and laboratory geneticist. The authors thank Cancéropôle Grand Sud-Ouest for providing clinical annotations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.