Article Text
Abstract
Objective Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data.
Design Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks.
Results The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2×10−16), confirmed in external validation sets (Sweden p=1.2×10−6, Finland p=2×10−5). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk.
Conclusion Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
- Genetic
- risk
- prediction
- colorectal cancer
- cancer genetics
- molecular genetics
- cancer susceptibility
- surgery for IBD
- colorectal cancer screening
- genetics
- colorectal cancer genes
- family cancer
- cancer epidemiology
- genotype
- IBD—genetics
- gallstones
- gallstone disease
- gallstone disease
- fatty liver
- epidemiology
- colon carcinogenesis
- molecular biology
- cancer epidemiology
- cancer prevention
- cancer epidemiology
- cancer
- cell biology
- endocrine tumours
- gastrointestinal neoplasia
- gene mutation
- colorectal neoplasia
- pancreatic cancer
Statistics from Altmetric.com
- Genetic
- risk
- prediction
- colorectal cancer
- cancer genetics
- molecular genetics
- cancer susceptibility
- surgery for IBD
- colorectal cancer screening
- genetics
- colorectal cancer genes
- family cancer
- cancer epidemiology
- genotype
- IBD—genetics
- gallstones
- gallstone disease
- gallstone disease
- fatty liver
- epidemiology
- colon carcinogenesis
- molecular biology
- cancer epidemiology
- cancer prevention
- cancer epidemiology
- cancer
- cell biology
- endocrine tumours
- gastrointestinal neoplasia
- gene mutation
- colorectal neoplasia
- pancreatic cancer
Footnotes
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MGD and AT are joint first authors. HC, IT and RSH are joint last authors.
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Funding Edinburgh: Work was supported by grants from Cancer Research UK (C348/A12076 and the Bobby Moore Fund), Scottish Government Chief Scientist Office (K/OPR/2/2/D333, CZB/4/94), Medical Research Council (G0000657-53203), Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity.org.uk). Cambridge: SEARCH is funded by a program grant from Cancer Research UK. TK was funded by the Foundation Dr Henri Dubois-Ferriere Dinu Lipatti. Kiel/Greifswald: Supported by the German National Genome Research Network (NGFN) through the PopGen biobank (BmBF 01GR0468) and the National Genotyping Platform. Further support through the MediGrid and services@medigrid projects (01AK803G, 01IG07015B). SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Heidelberg: Support from German Research Council (Deutsche Forschungsgemeinschaft) (BR 1704/6-1, BR 1704/6-3, CH 117/1-1) and the German Federal Ministry for Education and Research (01 KH 0404). Sweden: Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, The Swedish Cancer Society, The Stockholm Cancer Foundation and The Swedish Research Council. Colon-CFR: Grant support NIH/NCI U01CA122839. Spain: Supported by grants from Fondo de Investigación Sanitaria/FEDER (06/1384, 06/1712, 08/0024, 08/1276), Xunta de Galicia (PGIDIT07PXIB9101209PR), Fundación de Investigación Médica Mutua Madrileña (CRP and SCB), Ministerio de Educación y Ciencia (SAF 07-64873), Asociación Española contra el Cáncer (Fundación Científica and Junta de Barcelona), Fundación Olga Torres (SCB) and Acción Transversal de Cáncer (Instituto de Salud Carlos III). CIBERER and CIBEREHD are funded by the Instituto de Salud Carlos III. SCB is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070). We acknowledge the Santiago de Compostela and Barcelona branches of the Spanish National Genotyping Centre (CeGen) for genotyping. Finland: Grant support from Academy of Finland (Finnish Centre of Excellence Program 2006-2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission (9LSHG-CT-2004-512142). Canada: Cancer Care Ontario (host organisation to the ARCTIC Genome Project) acknowledges project funding by Genome Canada through the Ontario Genomics Institute, by Génome Québec, the Ministere du Dévelopement Économique et Régional et de la Recherche du Québec and the Ontario Institute for Cancer Research. Additional funding from National Cancer Institute of Canada (NCIC) through the Cancer Risk Assessment (CaRE) Program Project Grant. The work was supported through collaboration and cooperative agreements with the Colon Cancer Family Registry and PIs, supported by the National Cancer Institute, National Institutes of Health under RFA CA-95-011, including the Ontario Registry for Studies of Familial CRC (U01 CA076783). TJH and BWZ hold Senior Investigator Awards from the Ontario Institute for Cancer Research through generous support from the Ontario Ministry of Research and Innovation. Oxford: The work was supported by Cancer Research UK and the Bobby Moore Fund (C1298/A8362). Additional funding provided by the European Union (CPRB LSHC-CT-2004-503465), and CORE (http://www.corecharity.org.uk). IT is supported by the Oxford Biomedical Research Centre. The work was also supported by the Oxford Biomedical Research Centre and funded by the Medical Research Council. ICR, London: Grant support from Bobby Moore Cancer Cancer Research UK (C1298/A8362), CORE and the European Commission (QLG2-CT-2001-01861). SL was in receipt of a PhD studentship from Cancer Research UK and IC a Clinical Training Fellowship from St. George's Hospital.
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Competing interests All authors, and the corresponding author on their behalf, declare that they have no competing interests and the corresponding author acts as guarantor for all authors.
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Ethics approval Ethics approval was provided by all relevant ethics research committees and IRBs.
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Provenance and peer review Not commissioned; internally peer reviewed.
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Data sharing statement Summary data will be made available on request. Individual level data may be shared on a collaborative basis but measures will be taken to protect research subject identity over and above conventional anonymisation.