MicroRNA Related Polymorphisms and Breast Cancer Risk

Peer reviewe

Severe neonatal echovirus 20 infection charactirized by hepatic failure

Contains fulltext : 24880___.PDF (publisher's version ) (Open Access

Correction to: Age-Related Effects of Bariatric Surgery on Early Atherosclerosis and Cardiovascular Risk Reduction

Frederik H. W. Jonker and Vera A. A. van Houten contributed equally to this work

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.Peer reviewe

Breast cancer hypothesis: a single cause for the majority of cases

STUDY OBJECTIVE—The main cause of breast cancer remains unknown. Numerous causal factors or predisposing conditions have been proposed, but account for only a small percentage of the total disease. The current search for multiple causes is unavailing. This report explores whether any single aetiological agent may be responsible for the majority of cases, and attempts to define its properties.
METHODS—Examination of all relevant epidemiological and biological evidence.
MAIN RESULTS—Genetic inheritance is not the main cause of breast cancer because most cases are sporadic, there is a low prevalence of family history, and genetically similar women have differing rates after migration. Environmental exposure, such as pollution by industrialisation, is not a major cause, as deduced from a spectrum of epidemiological data. The possibility of infection as cause is not persuasive as there is no direct biological evidence and no epidemiological support. Oestrogen status is closely related to breast cancer risk, but there are numerous inconsistencies and paradoxes. It is suggested that oestrogens are not the proximate agent but are promoters acting in concert with the causal agent. Dietary factors, and especially fat, are associated with the aetiology of breast cancer as shown by intervention and ecological correlation studies, but the evidence from case-control and cohort studies is inconsistent and contradictory.
CONCLUSIONS—The hypothesis that best fits the epidemiological data is that dietary fat is not itself the causal agent, but produces depletion of an essential factor that is normally protective against the development of breast cancer. Many of the observed inconsistencies in the epidemiology are explainable if deficiency of this agent is permissive for breast cancer to develop. Some properties of the putative agent are outlined, and research investigations proposed.


Keywords: breast cance

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer