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Inherited predisposition to colorectal cancer: towards a more complete picture
  1. Emma Short1,
  2. Laura E Thomas1,
  3. Joanna Hurley2,
  4. Sian Jose3,
  5. Julian R Sampson1
  1. 1Institute of Cancer and Genetics, Cardiff University, Heath Park Campus, Cardiff, UK
  2. 2Department of Gastroenterology, Cwm Taf University Health Board, Prince Charles Hospital, Merthyr Tydfil, UK
  3. 3Institute of Medical Genetics, Cardiff and Vale Health Board, Cardiff, UK
  1. Correspondence to Professor Julian R Sampson, Institute of Cancer and Genetics, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, UK; sampson{at}


Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%–35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.

  • Cancer: colon
  • Clinical genetics
  • Gastroenterology
  • Genetics

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