Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

This corrects the article DOI: 10.1038/ncomms5999

Quality assurance of axillary radiotherapy in the EORTC AMAROS trial 10981/22023: the dummy run

Purpose: To assess and if needed improve the compliance of participating institutions to the radiotherapy guidelines of the EORTC AMAROS trial 10981/22023 comparing axillary radiotherapy to axillary surgery in sentinel node positive patients with early stage breast cancer. Materials and methods: A transverse contour and a frontal view radiograph of the axillary region of a 'dummy' patient were sent to all institutions intending to participate in the trial with the request to produce a radiotherapy treatment plan according to the protocol guidelines. Additional information on dose prescription, the treatment technique and field matching with breast fields and internal mammary lymph node fields was requested in a questionnaire. Results: Eighteen institutions have performed the dummy run. At first assessment, the dose was not specified according to the protocol in seven cases, while two institutions did not comply with the dose prescription of 50 Gy in 25 fractions. Dose heterogeneity was over 20% in 10 institutions, caused by the use of a two-field technique in eight cases. Ten institutions did not apply special techniques to obtain non-overlapping match planes. In 10 cases, one or more field borders or blocks were positioned incorrectly. Following recommendations from the quality assurance committee given to the participating institutions on an individual basis, 10 institutions adapted their technique. Thereafter, 16 institutions could be accepted for trial participation. Conclusions: A number of potential protocol deviations were found at first assessment. Since recommendations led to a large number of adaptations by the participants, a considerable improvement in protocol compliance and inter-institutional consistency was achieved. (C) 2003 Elsevier Ireland Ltd. All rights reserve

Cause-specific Mortality in a Population-based Cohort of 9799 Women Treated for Ductal Carcinoma in Situ

Objective: To assess cause-specific mortality in women treated for ductal carcinoma in situ (DCIS). Background: From screening and treatment perspective, it is relevant to weigh the low breast cancer mortality after DCIS against mortality from other causes and expected mortality in the general population. Methods: We conducted a population-based cohort study comprising 9799 Dutch women treated for primary DCIS between 1989 and 2004 and estimated standardized mortality ratios (SMRs). Results: After a median follow up of 9.8 years, 1429 patients had died of whom 284 caused by breast cancer (2.9% of total cohort). DCIS patients 50 had significantly lower mortality (SMR 0.9; 95% CI: 0.8-0.9). Overall, the risk of dying from general diseases and cancer other than breast cancer was lower than in the general population, whereas breast cancer mortality was increased. The SMR for breast cancer decreased from 7.5 (95% CI: 5.9-9.3) to 2.8 (95% CI: 2.4-3.2) for women aged 50 years, respectively. The cumulative breast cancer mortality 10 years after DCIS was 2.3% for women 50 years treated for DCIS between 1999 and 2004. Conclusions: DCIS patients >50 years had lower risk of dying from all causes combined compared with the general female population, which may reflect differences in health behavior. Women with DCIS had higher risk of dying from breast cancer than the general population, but absolute 10-year risks were low