Citations

Abstract Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases. In vitro, glycogen synthase kinase-3 (GSK-3), extracellular signal-related kinase-1 and -2, and mitogen-activated protein kinases, p38 kinase and c-jun N-terminal kinase, all phosphorylate many of these sites, although with different efficiencies for particular sites. Phosphorylation studies in transfected cells and neurons show that GSK-3 phosphorylates tau more extensively than do these other proline-directed kinases. Mutations in tau have been shown to affect in vitro phosphorylation of tau by GSK-3. The Arg406-->Trp (R406W) tau mutation also affects tau phosphorylation in cells.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P =0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P =0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P =0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Abstract Intro: Male BC is a rare disease (<1% male tumors); knowledge is limited and management extrapolated from female BC. An international consortium, coordinated by EORTC and TBCRC, was created to better characterize and manage this disease, with 3 parts: 1) retrospective joint analysis 2) prospective registry 3) clinical trial(s). We report 1st results of part 1. Methods: Joint analysis of male BC pts with available FU & FFPE samples, treated in 1990-2010, in 23 centers from 9 countries. Clinical data, long term outcomes, local pathology were centrally analyzed at EORTC. FFPE samples were analyzed at 3 central labs (UK, NL, US) for histology, grade, ER, PR, AR, HER-2, Ki67. Cut-off for positivity: Allred score ≥ 3 for ER/ AR/PR; 20% for Ki67; ASCO-CAP for HER2. Outcome data (OS & RFS) analyzed per Kaplan Meier, p-values correspond to logrank test, CI’s by Brookmeyer & Crowley. Reported % use number of non-missing values as denominator. Results: 1822 pts enrolled; 349 (19%) ineligible (no valid central lab assessment); of 1473 eligible pts (1384 from EU, 89 from US) 63% diagnosed in 2001-2010. Median age at diagnosis (Dx) was 68.5 ys. Of pts with known M status at Dx, 56 (5.1%) were M1; of 1046 M0 cases, 60% were N0 and 51% had T1 tumors at Dx; 4% of pts had BCS and 18% had SLNB; half received adjuvant RT. (Neo)adjuvant CT was used in 30% of M0 pts, most (44%) anthracycline-only; 77% of M0 pts received adjuvant ET, most tamoxifen (88.4%). Central pathology: 697 cases with central histology & grade (full series ongoing): 87% ductal, 53% grade 2. In 1473 pts, at least 1 biomarker centrally assessed; 92% ER highly+ (Allred 7-8), PR had wider variation (35% highly+); 87% AR highly+; 25% Ki67 high; 5% HER2pos. Using IHC surrogates: 58% Luminal A-like, 35% LuminalB-like/HER2neg, 6% LuminalB-like/HER2pos; 0.1% HER2pos/non-Luminal; 1% TNBC (16% not classified). Outcome: For 1046 M0 pts, median FU was 5.7 yrs (0-19.2); 63% alive at analysis; in 88% cause of death was reported, mainly 33% non-cancer and 28% progression(PD)/toxicity. Significant OS improvement over time is seen. 75% (42/56) M1 pts died, mainly due PD. In M0 pts, median OS (yrs) was significantly correlated with ER+ p=0.001 [Allred 0-2: 3.9 (0.1, 6.0); 3-6: 7.1 (4.7, 11.7); 7-8: 8.8 (8.3, 10.0)] & with PR+ p=0.022 [Allred 0-2: 7.3 (6.1, 10.3), 3-6: 8.0 (7.0, 9.3), 7-8: 9.5 (8.4, 12.8)]; less correlation for AR; no major differences for HER2 or Ki67. Median OS & grade (394 cases; full series ongoing): Grade1: 12.8 yrs (6.1-15.6); Grade2: 7.9 (6.5-10.7); Grade3: 9.3 (4.9-21.1). Median OS for IHC surrogates: 8.7 (7.8-9.7) for Luminal A; 8.3 (6.9-9.4) for Luminal B/HER-2neg; 9.3 years (5.9-21.1) for Luminal B/HER-2+. Similar results were seen for RFS. ER/PR/AR using histoscores will be presented. Conclusions: a) 56% pts had T1 tumors at Dx but only 4% had BCS; b) ER was highly + in >90% but adjuvant ET given in only 77% pts; c) Male BC is usually ER+, PR+ & AR+ and of Luminal A-like subtype (5% HER2pos & 1% TNBC); d) Significant improvement in OS over time; e) ER and PR (Allred) are prognostic (high expression/better prognosis), less for AR, not for Ki67 nor IHC surrogates; f) In-depth characterization of samples is ongoing. Funding: BCRF, EBCC Council, Pink Ribbon NL, BRO. Citation Format: Fatima Cardoso, John Bartlett, Leen Slaets, Carolien van Deurzen, Elise van Leewen-Stok, Peggy Porter, Barbro Linderholm, Ingrid Hedenfalk, Carolien Schroder, John Martens, Jane Bayani, Christi van Asperen, Melissa Murray, Clifford Hudis, Lavinia Middleton, Joanna Vermeij, Stephanie Peeters, Judith Fraser, Monica Nowaczyk, Isabel Rubio, Stefan Aebi, Catherine Kelly, Kathryn Ruddy, Eric Winer, Cecilia Nilsson, Lissandra Dal Lago, Larissa Korde, Kim Benstead, Danielle Van Den Weyngaert, Oliver Bogler, Theodora Goulioti, Nicolas Dif, Carlo Messina, Konstantinos Tryfonidis, Jan Bogaerts, Sharon Giordano. Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-05.