Citations

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.

Purpose To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. Methods A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective–retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. Results The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective–retrospective studies that evaluated the clinical utility of biomarkers. Recommendations In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient's goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

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 The International Classification of Headache Disorders provides criteria for the diagnosis and subclassification of migraine. Since there is no objective gold standard by which to test these diagnostic criteria, the criteria are based on the consensus opinion of content experts. Accurate migraine classifiers consisting of brain structural measures could serve as an objective gold standard by which to test and revise diagnostic criteria. The objectives of this study were to utilize magnetic resonance imaging measures of brain structure for constructing classifiers: (1) that accurately identify individuals as having chronic vs episodic migraine vs being a healthy control; and (2) that test the currently used threshold of 15 headache days/month for differentiating chronic migraine from episodic migraine. Methods Study participants underwent magnetic resonance imaging for determination of regional cortical thickness, cortical surface area, and volume. Principal components analysis combined structural measurements into principal components accounting for 85% of variability in brain structure. Models consisting of these principal components were developed to achieve the classification objectives. Tenfold cross validation assessed classification accuracy within each of the 10 runs, with data from 90% of participants randomly selected for classifier development and data from the remaining 10% of participants used to test classification performance. Headache frequency thresholds ranging from 5‐15 headache days/month were evaluated to determine the threshold allowing for the most accurate subclassification of individuals into lower and higher frequency subgroups. Results Participants were 66 migraineurs and 54 healthy controls, 75.8% female, with an average age of 36 +/− 11 years. Average classifier accuracies were: (1) 68% for migraine (episodic + chronic) vs healthy controls; (2) 67.2% for episodic migraine vs healthy controls; (3) 86.3% for chronic migraine vs healthy controls; and (4) 84.2% for chronic migraine vs episodic migraine. The classifiers contained principal components consisting of several structural measures, commonly including the temporal pole, anterior cingulate cortex, superior temporal lobe, entorhinal cortex, medial orbital frontal gyrus, and pars triangularis. A threshold of 15 headache days/month allowed for the most accurate subclassification of migraineurs into lower frequency and higher frequency subgroups. Conclusions Classifiers consisting of cortical surface area, cortical thickness, and regional volumes were highly accurate for determining if individuals have chronic migraine. Furthermore, results provide objective support for the current use of 15 headache days/month as a threshold for dividing migraineurs into lower frequency (ie, episodic migraine) and higher frequency (ie, chronic migraine) subgroups.

Abstract A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Objective To evaluate how many patients could have undergone partial nephrectomy ( PN ) rather than radical nephrectomy ( RN ) before and after neoadjuvant axitinib therapy, as assessed by five independent urological oncologists, and to study the variability of inter‐observer agreement. Patients and Methods Pre‐ and post‐systemic treatment computed tomography scans from 22 patients with clear cell renal cell carcinoma in a phase II neoadjuvant axitinib trial were reviewed by five independent urological oncologists. R.E.N.A.L. nephrometry score and κ statistics were calculated. Results The median R.E.N.A.L. nephrometry score changed from 11 before treatment to 10 after treatment ( P = 0.002). Five tumours with moderate complexity before axitinib treatment remained moderate complexity after treatment. Of 17 tumours with high complexity before axitinib treatment, three became moderate complexity after treatment. The overall κ statistic was 0.611. Moderate‐complexity κ was 0.611 vs a high‐complexity κ of 0.428. Before axitinib treatment the κ was 0.550 vs 0.609 after treatment. After treatment with axitinib, all five reviewers agreed that only five patients required RN (instead of eight before treatment) and that 10 patients could now undergo PN (instead of three before treatment). The odds of PN feasibility were 22.8‐times higher after treatment with axitinib. Conclusions There is considerable variability in inter‐observer agreement on the feasibility of PN in patients treated with neoadjuvant targeted therapy. Although more patients were candidates for PN after neoadjuvant axitinib therapy, it remains difficult to identify these patients a priori .

ABSTRACTBioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset.

Abstract Metastatic epidural spinal cord compression (MESCC) is an oncologic emergency and if left untreated, permanent paralysis will ensue. The treatment of MESCC is governed by disease, patient, and treatment factors. Patient's preferences and goals of care are to be weighed into the treatment plan. Ideally, a patient with MESCC is evaluated by an interdisciplinary team promptly to determine the urgency of the clinical scenario. Treatment recommendations must take into consideration the risk-benefit profiles of surgical intervention and radiotherapy for the particular individual's circumstance, including neurologic status, performance status, extent of epidural disease, stability of the spine, extra-spinal disease status, and life expectancy. In patients with high spinal instability neoplastic score (SINS) or retropulsion of bone fragments in the spinal canal, surgical intervention should be strongly considered. The rate of development of motor deficits from spinal cord compression may be a prognostic factor for ultimate functional outcome, and should be taken into account when a treatment recommendation is made. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.