3 years ago

A comprehensive analysis of polymorphic variants in steroid hormone and IGF-1 metabolism and risk of in situ breast cancer: results from the Breast and Prostate Cancer Cohort (BPC3) Consortium

Regina Ziegler, Susan M. Gapstur, Julie E. Buring, Graham G. Giles, Signe Borgquist, Peter Kraft, Roger L. Milne, Kay-Tee Khaw, Daniele Campa, Mia M. Gaudet, Rudolf Kaaks, Xiaohong R Yang, Carla H. van Gils, Antonia Trichopoulou, Kostas Tsilidis, Federico Canzian, Loic Le Marchand, Elisabete Weiderpass, I-Min Lee, David J. Hunter, Myrto Barrdahl, Stephen J. Chanock, Sara Lindström, Christopher Haiman
We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and IGF-1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was done using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom=3.05, 95%CI = 1.72-5.44, Phom= 1.47 × 10−4), MAST2-rs12124649 (ORhom=1.73, 95% CI =1.18-2.54, Phom= 5.24 × 10−3), and INSR-rs10500204 (ORhom= 1.96, 95% CI =1.44-2.67, Phom=1.68 × 10−5) were associated with increased risk of BCIS; however only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom=1.78, 95% CI =1.30-2.44, Phom= 3.23 × 10−4). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/ijc.31145

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