Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
BackgroundExosomal microRNAs (miRNAs) are promising candidate biomarkers for diagnosis or prognosis for breast cancer. We investigated the prognostic role of exosomal miRNAs in serum samples derived from patients with breast cancer and compared miRNA expression between serum and tumor tissues.MethodsThe miRNA profile derived from exosome between breast cancer patients with recurrence (n = 16) and without recurrence (n = 16) were compared by miRNA PCR array. Further, we examined the expression of miRNAs derived from tissues in the patients with breast cancer with (n = 35) and without recurrence (n = 39) by qRT-PCR.ResultsOf 384 miRNAs, three miRNAs (miR-338-3p, miR-340-5p, and miR-124-3p) were significantly upregulated and eight (miR-29b-3p, miR-20b-5p, miR-17-5p, miR-130a-3p, miR-18a-5p, miR-195-5p, miR-486-5p, and miR-93-5p) were significantly downregulated in the patients with recurrence. We evaluated the expression of the miRNAs in tumor tissues. The patients with recurrence had higher levels of miR-340 at their primary site as well as in the serum. In contrast, miR-195-5p, miR-17-5p, miR-93-5p, and miR-130a-3p, derived from tumor tissues that were downregulated in the serum from patients with recurrence, were higher in the patients with recurrence than in those with no recurrence. In logistic regression analysis, miR-340-5p, miR-17-5p, miR-130a-3p, and miR-93-5p were significantly associated with recurrence.ConclusionsSeveral exosomal miRNAs may be useful biomarkers to predict breast cancer recurrence. We show the different expression patterns of miRNAs between tumor tissues and serum. These findings may suggest selective mechanism of release of exosomal miRNAs by cancer cells to regulate their progression.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ~10% of excess familial risk of breast cancer in Asian populations.
Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 23 genetic variants identified in previous GWASs and conducted a case-control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Eleven single-nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4-5, 6-7, 8-9, and 10 or more were 1.33 (95% confidence interval, 1.00-1.80), 1.71 (1.26-2.30), 3.01 (1.97-4.58), and 8.69 (2.75-27.5), respectively (P (trend) = 1.9 × 10(-9)). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.6933, versus 0.6652 with the conventional risk factors only (P = 1.3 × 10(-4)). Population-attributable fraction of the risk score was 33.0%. In conclusion, we identified a genetic risk predictor of breast cancer in a Japanese population. Risk models which include a genetic risk score are possibly useful in distinguishing women at high risk of breast cancer from those at low risk, particularly in the context of targeted prevention.
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