title: Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives.
abstract: OBJECTIVE
  To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features.
  
  
  METHODS
  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.
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia Department of Molecular and Cellular Pathology, University of Queensland, Herston, Queensland, Australia Envoi Specialist Pathologists, Herston, Queensland, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: MacInnis
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Dite
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia.
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Clive Berghofer Cancer Research Centre, Herston, Queensland, Australia.
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA School of Public Health, University of Washington, Seattle, Washington, USA Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA School of Public Health, University of Washington, Seattle, Washington, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Stanford Cancer Institute, Stanford University, San Francisco, California, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada Cancer Care Ontario, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Veterans Affairs, Eastern Colorado Health Care System, University of Colorado School of Medicine, Denver, Colorado, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D055815:Young Adult