Associations between SNPs in the region surrounding rs9348512 on chromosome 6 and breast cancer risk.

<p>Results based on imputed and observed genotypes. The blue spikes indicate the recombination rate at each position. Genotyped SNPs are represented by diamonds and imputed SNPs are represented by squares. Color saturation indicates the degree of correlation with the SNP rs9348512.</p

Per allele hazard ratios (HR) and 95% confidence intervals (CI) of previously published breast cancer loci among <i>BRCA2</i> mutation carriers from previous reports and from the iCOGS array, ordered by statistical significance of the region.

1<p>Reporting status of the SNP is either previously reported or novel to this report.</p>2<p>p-value was calculated based on the 1-degree of freedom score test statistic.</p>3<p>rs311499 could not be designed onto the iCOGS array. A surrogate (r² = 1.0), rs311498, was included, however, and reported here.</p>4<p>Stronger associations were originally reported for the SNP, assuming a dominant or recessive model of the ‘risk allele’.</p

Breast cancer hazard ratios (HR) and 95% confidence intervals (CI) of novel breast cancer loci with P-values of association <10⁻⁵ among <i>BRCA2</i> mutation carriers.

1<p>P-value was calculated based on the 1-degree of freedom score test.</p

The <i>HMMR</i> locus and breast cancer risk in <i>BRCA1</i> mutation carriers.

<p>(<b>A</b>) Forest plots showing rs299290 HRs and 95% CIs (retrospective likelihood trend estimation) for participating countries (relatively small sample sets are not shown) ordered by sample size. Left and right panels show results for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers, respectively. The sizes of the rectangles are proportional to the corresponding country/study precision. (<b>B</b>) The rs299290-containing region, including the genes, variation and regulatory evidence mentioned in HMECs. Exons are marked by black-filled rectangles and the direction of transcription is marked by arrows in the genomic structure. The chromosome 5 positions (base pairs (bp)) and linkage disequilibrium structure from Caucasian HapMap individuals are also shown.</p

Gene expression interactions in breast cancer survival.

<p>(<b>A</b>) Kaplan–Meier survival curves based on categorization of <i>HMMR</i> (probe NM_012484) and <i>AURKA</i> (NM_003600) expression in tertiles (low, medium or high expression). For simplicity, only the tertiles for “high” <i>AURKA</i> are shown. The tumours with high expression levels for both genes were not those with the poorest prognosis. (<b>B</b>) Kaplan–Meier survival curves based on categorization of <i>HMMR</i> (NM_012484) and <i>TUBG1</i> (NM_016437) expression in tertiles (low, medium or high expression). For simplicity, only the tertiles for “high” <i>HMMR</i> are shown. The cases with high expression levels for both genes were those with the poorest prognosis.</p

Potential GxG associated with breast cancer risk in <i>BRCA1/2</i> mutation carriers.

<p>*Each estimate is derived from the interaction term of a Cox regression model.</p><p>Potential GxG associated with breast cancer risk in <i>BRCA1/2</i> mutation carriers.</p

Mapping of the 17q21 locus.

<p><i>Top 3 panels:</i> P-values of association (−log₁₀ scale) with ovarian cancer risk for genotyped and imputed SNPs (1000 Genomes Project CEU), by chromosome position (b.37) at the 17q21 region, for <i>BRCA1</i>, <i>BRCA2</i> mutation carriers and combined. Results based on the kinship-adjusted score test statistic (1 d.f.). <i>Fourth panel:</i> Genes in the region spanning (43.4–44.9 Mb, b.37) and the location of the most significant genotyped SNPs (in red font) and imputed SNPs (in black font). <i>Bottom panel:</i> Pairwise r² values for genotyped SNPs on iCOG array in the 17q21 region covering positions (43.4–44.9 Mb, b.37).</p

Predicted breast and ovarian cancer absolute risks for <i>BRCA1</i> mutation carriers at the 5^th, 10^th, 90^th, and 95^th percentiles of the combined SNP profile distributions.

<p>The minimum, maximum and average risks are also shown. Predicted cancer risks are based on the associations of known breast or ovarian cancer susceptibility loci (identified through GWAS) with cancer risk for <i>BRCA1</i> mutation carriers and loci identified through the present study. Breast cancer risks based on the associations with: 1q32, 10q25.3, 19p13, 6q25.1, 12p11, <i>TOX3</i>, 2q35, <i>LSP1</i>, <i>RAD51L1</i> (based on HR and minor allele frequency estimates from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t001" target="_blank">Table 1</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t002" target="_blank">Table 2</a>, and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212.s016" target="_blank">Table S4</a>) and <i>TERT </i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Bojesen1" target="_blank">[31]</a>. Ovarian cancer risks based on the associations with: 9p22, 8q24, 3q25, 17q21, 19p13 (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t001" target="_blank">Table 1</a>) and 17q21.31, 4q32.3 (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t002" target="_blank">Table 2</a>). Only the top SNP from each region was chosen. Average breast and ovarian cancer risks were obtained from published data <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Antoniou10" target="_blank">[25]</a>. The methods for calculating the predicted risks have been described previously <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Antoniou11" target="_blank">[28]</a>.</p

Study design for selection of the SNPs and genotyping of <i>BRCA1</i> samples.

<p>GWAS data from 2,727 <i>BRCA1</i> mutation carriers were analysed for associations with breast and ovarian cancer risk and 32,557 SNPs were selected for inclusion on the iCOGS array. A total of 11,705 <i>BRCA1</i> samples (after quality control (QC) checks) were genotyped on the 31,812 <i>BRCA1</i>-GWAS SNPs from the iCOGS array that passed QC. Of these samples, 2,387 had been genotyped at the SNP selection stage and are referred to as “stage 1” samples, whereas 9,318 samples were unique to the iCOGS study (“Stage 2” samples). Next, 17 SNPs that exhibited the most significant associations with breast and ovarian cancer were selected for genotyping in a third stage involving an additional 2,646 <i>BRCA1</i> samples (after QC).</p

Associations with SNPs at the novel 17q21 region with ovarian cancer risk for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers.

*<p>HRs estimated under the single disease risk model.</p