Breast cancer susceptibility variants alter risks in familial disease
- Ayşe Latif1,
- Kristen D Hadfield1,
- Stephen A Roberts2,
- Andrew Shenton1,
- Fiona Lalloo1,
- Graeme C M Black1,
- Anthony Howell3,
- D Gareth Evans1,3,
- William G Newman1
- 1Department of Medical Genetics, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK
- 2Health Research Methodology Group, University of Manchester, Manchester, UK
- 3The Nightingale Centre & Genesis Prevention Centre, Wythenshawe Hospital, Manchester, UK
- Correspondence to Professor D G Evans, Department of Medical Genetics, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester M13 0JH, UK; gareth.evans{at}cmft.nhs.uk
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Contributors All authors have reviewed and contributed to the manuscript except AS, who died in sudden unexpected circumstances in 2008. He contributed to data collection and collation.
- Received 23 February 2009
- Revised 15 June 2009
- Accepted 29 June 2009
- Published Online First 16 July 2009
Abstract
Background Recent candidate and genome-wide association studies have identified variants altering susceptibility to breast cancer.
Objective To establish the relevance of these variants to breast cancer risk in familial breast cancer cases both with and without BRCA1 or BRCA2 (BRCA1/2) mutations.
Methods A cohort of unrelated individuals with breast cancer due to the presence of either BRCA1 (121) or BRCA2 mutations (109) and individuals with familial breast cancer not due to BRCA1/2 mutations (722) were genotyped using Taqman SNP Genotyping Assays. Allele frequencies were compared with an ethnically and gender-matched group (436).
Results A synonymous variant (Ser51) in TOX3 (previously TNRC9) was associated with an increased risk of breast cancer (OR=1.82, p<0.001) in BRCA2 mutation carriers. The associations for FGFR2 (OR=1.20, p=0.046), TOX3 (OR=1.5, p<0.001), MAP3K1 (OR=1.26 p=0.03), CASP8 (OR=0.73 p=0.02) and the chromosome 8-associated SNP (OR=1.31, p=0.004) were replicated in individuals without BRCA1/2 mutations. In addition, homozygote carriers of MAP3K1 variants were shown to have a significantly lower Manchester Score (mean 13.8–17.6, p=0.003), whereas individuals carrying one or two copies of the FGFR2 variant had a higher Manchester Score (mean 17.5–17.9, p=0.01).
Conclusions This study confirms that susceptibility variants in FGFR2, TOX3 and MAP3K1 and on chromosome 8q are all associated with increased risk of cancer in individuals with a family history of breast cancer, whereas CASP8 is protective in this context. The level of risk is dependent on the strength of the family history and the presence of a BRCA1/2 mutation and contributes to the understanding of the use of these variants in clinical risk prediction.
- Cancer: breast
- familial breast cancer
- genome wide association study
- genetics
- FGFR2
- Manchester Score
- TOX3/TNRC9
Footnotes
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An additional table is published only at http://jmg.bmj.com/content/vol47/issue2
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Funding This study was funded by Genesis UK, who had no role in study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; nor in the decision to submit the manuscript for publication.
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Competing interests None.
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Ethics approval This study was conducted with the approval of the North Manchester Research Ethics Committee 08/H1006/77.
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Provenance and peer review Not commissioned; externally peer reviewed.
