Breast cancer susceptibility variants alter risks in familial disease. Issue 2 (16th July 2009)

• Record Type: Journal Article
• Authors: Latif, Ayşe; Hadfield, Kristen D; Roberts, Stephen A; Shenton, Andrew; Lalloo, Fiona; Black, Graeme C M; Howell, Anthony; Evans, D Gareth; Newman, William G
• Is Part Of: Journal of medical genetics. Volume 47:Issue 2(2010)
• Page Start: 126
• Page End: 131
• Publication Date: 2009-07-16
• Subjects: Cancer: breast -- familial breast cancer -- genome wide association study -- genetics -- FGFR2 -- Manchester Score -- TOX3/TNRC9; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2009.067256
• Languages: English
• ISSNs: 1468-6244

Abstract

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.