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Br J Cancer. 2012 Jan 17;106(2):389-96. doi: 10.1038/bjc.2011.461. Epub 2011 Nov 1.

Combined effect of low-penetrant SNPs on breast cancer risk.

Author information

1
Departments of Medical Microbiology and Clinical Chemistry, Lund University, SUS entrance 78, Malmö S-205 02, Sweden. sophia.harlid@med.lu.se

Abstract

BACKGROUND:

Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.

METHODS:

Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.

RESULTS:

Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)).

CONCLUSION:

The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

PMID:
22045194
PMCID:
PMC3261688
DOI:
10.1038/bjc.2011.461
[Indexed for MEDLINE]
Free PMC Article

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