Research article

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

Ummiye V Onay^1,2 , Kirsimari Aaltonen^3,4 , Laurent Briollais^1,5,6 , Julia A Knight^1,5,6 , Noel Pabalan¹ , Outi Kilpivaara⁴ , Irene L Andrulis^1,2,7,8,9 , Carl Blomqvist³ , Heli Nevanlinna⁴ and Hilmi Ozcelik^1,2,9

¹Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

²Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada

³Department of Oncology, Helsinki University Central Hospital, Finland

⁴Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Finland

⁵Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

⁶Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

⁷Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, Ontario, Canada

⁸Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

⁹Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

author email corresponding author email

BMC Cancer 2008, 8:6doi:10.1186/1471-2407-8-6

Published:	14 January 2008

Abstract

Background

Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.

Methods

In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.

Results

Here, we have shown that the high enzymatic activity genotype of CCND1^High (AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium (MetVal) and the high enzymatic activity of COMT^High (ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High (ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: 2.22, 95%CI (1.49–3.28)] and Finland [OR: 1.73, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.

Conclusion

Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.