A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 ... Show moreA combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30-to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 x 10(-31)). Show less
Park, J.; Choi, J.Y.; Choi, J.; Chung, S.; Song, N.; Park, S.K.; ... ; NBCS Collaborators 2021
Simple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors... Show moreSimple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors combine with environmental factors to influence risk. However, previous studies have not found or found only a few interactions by using SNPs which were discovered from genome-wide association studies and have been conducted, for the most part, within European populations. In this study, we focused on estrogen-related lifestyle factors that have been identified for breast cancer, including several well-established reproductive factors that are mediated by hormonal mechanisms. We aimed to examine whether there are any gene and environmental factor interactions related to estrogen exposure or metabolism using a candidate approach in Korean women. We found two interactions in this study, although they were not replicated in the independent large consortium data. These findings suggest specificity in Koreans for breast cancer risk.In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 x 10(-3)). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 x 10(-4)). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk. Show less
Ghoussaini, M.; Edwards, S.L.; Michailidou, K.; Nord, S.; Lari, R.C.S.; Desai, K.; ... ; Australian Ovarian Canc Management 2018
