Oligogenic Determinism of Colorectal Cancer
Condition: Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional

Summary: 
      The majority of the clinical situations suggestive of an increased genetic risk for
      colorectal cancer (CRC) are not explained by a simple monogenic model. Our working hypothesis
      is that a fraction of clinical conditions suggestive of an increased genetic risk for CRC
      (familial aggregation, early age of tumour onset, development of multiple primary CRC) is due
      to the combination of a limited number of genetic variations, each conferring a moderate risk
      for CRC, but whose combination results into high risk.

      This study, which will be both retrospective and prospective, is an association study that
      will compare frequencies of selected genetic variations, alone or in combination, between
      patients (cases) whose clinical presentation is suggestive of an increased genetic risk but
      who do not present a known Mendelian form of CRC, and controls, in order to assess
      associations of these variations with non-Mendelian genetic forms of CRC. The inclusion
      criteria will be: CRC in two first degree relatives, one being diagnosed before 61 years of
      age; or CRC diagnosed before 51 years of age or advanced colorectal adenoma before 41 years
      of age; or multiple primary CRCs in the same individual, the first being diagnosed before 61
      years of age The exclusion criteria will be: Lynch syndrome, adenomatous polyposis and
      hamartomatous polyposis. The genetic variations which will be analyzed will include (i) SNPs
      detected by GWAS and associated to CRC. (ii) Risk factors corresponding to functional
      polymorphisms within candidate genes. (iii) Imbalance of the TGFbR1 allelic expression.
      Sample sizes were calculated to obtain 80% power for an odds ratio of 2.5 since the aim of
      this study is to determine genetic variations conferring a moderate risk. In order to cover
      all these possibilities and to have reasonable even for the genetic variations with low
      frequency below 0.03 or high frequency above 0.90, the target sample size was set at 700
      cases and 350 controls. The recruitment of patients will be performed at the national level
      by the cancer genetics departments ensuring a correct evaluation of the personal and familial
      history and the French molecular diagnosis laboratories network ensuring in routine the
      analysis of the main genes involved in CRC. The control population will be composed of
      healthy subjects of Caucasian origin between 45 and 60 years of age, without personal or
      familial history among their first-degree relatives of colorectal tumours.

      Demonstration that the combination of a limited number of genetic variations, each conferring
      a moderate risk for CRC, results into high risk would allow to base, in selected families,
      the evaluation of risk in relatives and indication of colonoscopy on the analysis of gene
      variants the combination of which would confer a high risk. This study will confirm or
      invalidate the contribution of aTGFbR1 allelic expression imbalance in the determinism of
      early-onset CRC and familial aggregation of CRC. The demonstration of the involvement in CRC
      genetic variations with strong effect of specific combinations should be of interest for our
      general understanding of the molecular basis of CRC.
    


Intervention name(s): Blood drawn
Intervention type(s): Genetic
Intervention description(s): Blood drawn for patient
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Colo-Rectal Cancer