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Gut 56:1453-1459 doi:10.1136/gut.2007.126870
  • Recent advances in basic science

Serrated pathway colorectal cancer in the population: genetic consideration

  1. Joanne Young1,
  2. Mark Jenkins2,
  3. Susan Parry3,
  4. Bruce Young4,
  5. Derek Nancarrow5,
  6. Dallas English2,
  7. Graham Giles6,
  8. Jeremy Jass7
  1. 1Familial Cancer Laboratory, QIMR, Herston, Queensland, Australia
  2. 2MEGA Epidemiology, University of Melbourne, Victoria, Australia
  3. 3Middlemore Hospital, Auckland, New Zealand
  4. 4Faculty of Education, QUT, Kelvin Grove, Queensland, Australia
  5. 5Human Genetics Laboratory, QIMR, Herston, Queensland, Australia
  6. 6Victorian Anti-Cancer Council, Victoria, Australia
  7. 7Department of Cellular Pathology, St Marks Hospital, Harrow, UK
  1. Correspondence to:
    Joanne Young
    QIMR 300 Herston Road, Herston Q 4006, Australia; Joanne.Young{at}qimr.edu.au
  • Accepted 12 May 2007
  • Revised 9 May 2007
  • Published Online First 12 June 2007

Abstract

A significant proportion of colorectal cancer (CRC) develops through the serrated neoplasia pathway. Such tumours show a distinctive molecular phenotype of somatic BRAF mutations and widespread concordant methylation events in CpG islands (CIMP). These features are also observed in the polyps developing in individuals with hyperplastic polyposis syndrome (HPS). In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC. Observations of rare affected sibships including identical twins, suggest a recessive or co-dominant mode of inheritance. In addition, up to 50% of individuals with HPS report a family history of CRC. At a population level, recent work has demonstrated that patients with serrated pathway cancers characterised by BRAF mutation are four times more likely to have a family history of CRC than patients with common CRC. These findings suggest an increased genetic predisposition for serrated pathway CRC in the wider population. We propose that HPS results from the inheritance of two putative co-dominant alleles in approximately 1 in 2000 individuals. Therefore carriers of one co-dominant allele may number up to 1 in 25, and it is likely that these carriers are at increased risk of CRC, accounting for, at least in part, the burden of serrated pathway CRC in the population. This proposition may have important implications for screening and prevention of CRC in individuals who have an increased risk for development of serrated pathway cancers, namely those with multiple, proximal, large or advanced serrated polyps, and their relatives.

Footnotes

  • Competing interests: None.