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Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives
  1. Aung Ko Win1,
  2. Daniel D Buchanan2,
  3. Christophe Rosty2,3,4,
  4. Robert J MacInnis1,5,
  5. James G Dowty1,
  6. Gillian S Dite1,
  7. Graham G Giles1,5,
  8. Melissa C Southey6,
  9. Joanne P Young2,
  10. Mark Clendenning2,
  11. Michael D Walsh2,
  12. Rhiannon J Walters2,
  13. Alex Boussioutas7,8,9,
  14. Thomas C Smyrk10,
  15. Stephen N Thibodeau10,
  16. John A Baron11,
  17. John D Potter12,13,14,
  18. Polly A Newcomb12,13,
  19. Loïc Le Marchand15,
  20. Robert W Haile16,
  21. Steven Gallinger17,18,
  22. Noralane M Lindor19,
  23. John L Hopper1,
  24. Dennis J Ahnen20,
  25. Mark A Jenkins1
  1. 1Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
  2. 2Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia
  3. 3Department of Molecular and Cellular Pathology, University of Queensland, Herston, Queensland, Australia
  4. 4Envoi Specialist Pathologists, Herston, Queensland, Australia
  5. 5Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria, Australia
  6. 6Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
  7. 7Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
  8. 8Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  9. 9Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
  10. 10Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  11. 11Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  12. 12Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  13. 13School of Public Health, University of Washington, Seattle, Washington, USA
  14. 14Centre for Public Health Research, Massey University, Wellington, New Zealand
  15. 15University of Hawaii Cancer Center, Honolulu, Hawaii, USA
  16. 16Stanford Cancer Institute, Stanford University, San Francisco, California, USA
  17. 17Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  18. 18Cancer Care Ontario, Toronto, Ontario, Canada
  19. 19Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona, USA
  20. 20Department of Veterans Affairs, Eastern Colorado Health Care System, University of Colorado School of Medicine, Denver, Colorado, USA
  1. Correspondence to Dr Mark Jenkins, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Level 3, 207 Bouverie Street, The University of Melbourne, Melbourne, VIC 3010 Australia; m.jenkins{at}


Objective To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features.

Design We studied a cohort of 33 496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28 156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands. We compared CRC risk for first-degree relatives stratified by the absence or presence of specific tumour molecular pathology features in probands across each of these four groups and for all groups combined.

Results Compared with first-degree relatives of MMR-proficient CRC cases, a higher risk of CRC was estimated for first-degree relatives of CRC cases with suspected Lynch syndrome (HR 2.06, 95% CI 1.59 to 2.67) and with Lynch syndrome (HR 5.37, 95% CI 4.16 to 6.94), but not with MMR-deficient non-Lynch syndrome (HR 1.04, 95% CI 0.82 to 1.31). A greater risk of CRC was estimated for first-degree relatives if CRC cases were diagnosed before age 50 years, had proximal colon cancer or if their tumours had any of the following: expanding tumour margin, peritumoral lymphocytes, tumour-infiltrating lymphocytes or synchronous CRC.

Conclusions Molecular pathology features are potentially useful to refine screening recommendations for first-degree relatives of CRC cases and to identify which cases are more likely to be caused by genetic or other familial factors.

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