Citations

Abstract Since most GWAS hits fall in non-coding regions of the genome and long non-coding RNAs (lncRNAs) are emerging as drivers of carcinogenesis, we hypothesized that SNPs in lncRNAs influence epithelial ovarian cancer (EOC) risk. A comprehensive lncRNA database (lncRNA db) that contained 104 human lncRNAs when downloaded in November 2011 was used to identify 1,737 variants in 63 unique lncRNAs that were represented in three genome-wide association studies from North America, the United Kingdom, and Poland (3,995 EOC cases and 3,277 controls of European background). SNPs with MAF <5% were excluded, and missing genotypes were inferred with Mach using the HapMap CEU population. Unconditional logistic regression treating alternate alleles as an ordinal variable was used to evaluate individual SNP-EOC risk associations. Subgroup analysis was conducted for serous adenocarcinomas (N= 2,066), the main histologic subtype of EOC. Models were adjusted for study and European ancestry using the first two principal components (PCs). We reduced correlated signals (r2 ≥ 0.8) within each lncRNA and kept the most statistically significant variants based on Wald tests, resulting in 651 SNPs for further analyses. Fisher's product method was used to aggregate evidence of multiple variants within each lncRNA using 10,000 permutations. To adjust for multiple comparisons, a false discovery rate (FDR) of 10% was used. A replication phase was carried out for top-ranked SNPs from an additional 9,854 EOC cases (5,802 serous) and 17,633 controls genotyped through an international effort known as the Collaborative Oncological Gene-Environment study (COGS). Four lncRNAs, WT1-AS (p = 0.005, n = 2 SNPs), Hoxa11as (p = 0.013, n = 2), AK082072 (p = 0.016, n = 4) and H19 (p = 0.020, n = 2), were significantly associated with EOC risk among all histologies (FDR ≤ 10%). The SNP in WT1-AS most significantly associated with EOC risk was rs3809061 (T>C) (minor allele frequency= 36%, odds ratio (OR) = 0.91, CI: 0.84-0.97, p = 0.008). Among serous cases, rs3809061 was also protective (OR = 0.92, p = 0.04). These findings were replicated by a correlated SNP rs2301250 (r2 = 0.84) evaluated in COGS among serous cases (OR = 0.94, CI: 0.90-0.99, p = 0.009) and less significant among all histologies (OR = 0.96, CI: 0.93-1.00, p = 0.054). We further interrogated its functional role by performing an expression quantitative trait locus analysis on WTI-AS mRNA expression using the Cancer Genome Atlas (TCGA) data (N = 462 serous cases). WT1-AS expression was significantly higher among carriers of the variant allele (compared to TT homozygotes) using the Mann-Whitney U test (p = 0.001). WT1-AS is the antisense and possible regulator of WT1, a tumor suppressor gene reported to be prognostic in advanced EOC. These findings implicate germline lncRNA variants associated with EOC risk that merit further investigation. Citation Format: Yian Ann Chen, Zhihua Chen, Jennifer Permuth-Wey, Ya-Yu Tsai, Hui-Yi Lin, Xiaotao Qu, Kate Lawrenson, David Fenstermacher, Catherine M. Phelan, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Rebecca Sutphen, Michael J. Birrer, Nicolas Wentzensen, Joellen M. Schildkraut, Ellen L. Goode, Paul Pharoah, Thomas Sellers. Variants in long non-coding RNAs are associated with epithelial ovarian cancer risk in a pooled analysis of three genome-wide association studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4579. doi:10.1158/1538-7445.AM2013-4579

Abstract Hyperactive ERBB/K-RAS signaling is a major menace that drives aggressive tumor growth and metastasis in human cancer. Currently, there are no effective ways to treat late-stage and relapsed human cancers that have oncogenic ERBB/K-RAS mutations that often confer drug resistance, aggressive tumor growth, systemic metastasis, and poor clinical outcome. Therefore, finding novel approaches and new drug targets to inhibit oncogenic ERBB/K-RAS activation is an urgent goal and the major challenge in cancer therapy and treatment. Instead of targeting an upstream signaling module such as EGFR/HER2/KRAS/B-RAF, we targeted the most downstream signaling module in the EGFR/HER2/K-RAS pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper EGFR/HER2/K-RAS/B-RAF signal transduction. Guided by the insights and fundamental principles learned from the Drosophila RAS signaling pathway, we conducted preclinical studies to dissect SIAH function in the context of ERBB/K-RAS-mediated tumorigenesis and metastasis in human cancer cells and human cancer biospecimens. We found that (1) SIAH is a great prognostic and predictive biomarker for human cancer, and (2) inhibiting SIAH function is highly effective to block tumorigenesis and metastasis against the well-established, late-stage and metastatic pancreatic cancer and triple negative breast cancer (TNBC). These findings demonstrate that SIAH is an attractive and logical new therapeutic target for novel anti-ERBB/oncogenic K-RAS and anticancer therapy in human cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic ERBB/K-RAS activation in human cancer cells. Using anti-SIAH molecules to block K-RAS signaling in human cancer is an excellent example of science going “from the bench (basic research in fruit flies) to the bedside (preclinical studies and ultimately clinical trials)”. As a highly evolutionarily conserved E3 ligase and the most downstream “gatekeeper” of EGFR/HER2/K-RAS/B-RAF signaling pathway, SIAH is uniquely and logically positioned to become a next-generation anti-ERBB/anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles' heel in human cancer. Knowledge gained from our study has great promise and immediate translational values. Anti-SIAH-based small molecule inhibitors may aid in expanding our arsenal of novel anticancer therapies. By attacking the oncogenic ERBB/K-RAS/B-RAF pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we will be in a position to control the late-stage, relapsed and metastatic human cancers. If successful, we hope to develop anti-SIAH-based therapy and translate our findings to the cancer clinics to treat cancer patients with metastatic diseases in the near future. Citation Format: Minglei Bian, Yang Liao, Vasilena Zheleva, Xiaofei Gao, Zena M. Urban, Monicah M. Njogu, Justin J. Odanga, Andrew J. Isbell, Rebecca L. Schmidt, Rie Takahashi, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen, Amy H. Tang. Attacking the most downstream “gatekeeper” signaling module in the oncogenic ERBB/K-RAS signaling pathway to block tumorigenesis and metastasis in human cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C62.

AimsThe pathogenesis of intraosseous mucoepidermoid carcinoma (IMEC) remains unknown. Coexistence with odontogenic cysts (ODC) has been reported in 32–48% of IMEC. Furthermore, prosoplastic mucous cells are often seen in the epithelial lining of ODCs. MECT1–MAML2 fusion transcripts have been identified in >66% of salivary gland MEC cases. The aim of this study was to investigate the presence of MAML2 rearrangement in ODCs featuring mucous prosoplasia.Methods and resultsTen cases of ODC with a mucous cell component and three cases of IMEC were evaluated using fluorescence in‐situ hybridization. All cases occurred in the mandible. The ODCs exhibited a M:F ratio of 4:1 (mean age 49.2 years), while all IMECs occurred in women (mean age 68.3 years). All three IMECs demonstrated MAML2 rearrangement, in 26–61% of tumour cells. Successful hybridization was observed in nine of 10 cases of ODC. In two of these nine, there was MAML2 rearrangement in 12% and 24% of the lining epithelial cells, while three of the nine showed rearrangement in 7–8% of cells; the remaining four cases were negative.ConclusionsWe identified MAML2 rearrangements in five of nine ODCs lined by mucus‐secreting cells. This suggests that at least a subset of ODCs with mucous prosoplasia are characterized by molecular events considered diagnostic for intraosseous and extraosseous MEC.

Abstract Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab, and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal, with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T polymorphisms in 1,325 patients from the N9831 clinical trial. Patients in arm A (N = 419) received chemotherapy only. Patients in arms B (N = 469) and C (N = 437) were treated with chemotherapy and trastuzumab (sequentially in arm B and concurrently in arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high-affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (P < 0.001), compared with the T carriers who did not (P = 0.81). The interaction between FCGR2B genotype and treatment was statistically significant (P = 0.03). Our analysis did not reveal an association between FcγR high-affinity genotypes and outcomes. However, it seems that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit. Cancer Immunol Res; 2(10); 962–9. ©2014 AACR.

Background and purposeSome recent studies in older, largely white populations suggest that vitamin D, measured by 25‐hydroxyvitamin D [25(OH)D], is important for cognition, but such results may be affected by reverse causation. Measuring 25(OH)D in late middle age before poor cognition affects behavior may provide clearer results.MethodsThis was a prospective cohort analysis of 1652 participants (52% white, 48% black) in the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study. 25(OH)D was measured from serum collected in 1993–1995. Cognition was measured by the delayed word recall test (DWRT), the digit symbol substitution test (DSST) and the word fluency test (WFT). Dementia hospitalization was defined by ICD‐9 codes. Adjusted linear, logistic and Cox proportional hazards models were used.ResultsMean age of participants was 62 years and 60% were female. Mean 25(OH)D was higher in whites than blacks (25.5 vs. 17.3 ng/ml, P < 0.001). Lower 25(OH)D was not associated with lower baseline scores or with greater DWRT, DSST or WFT decline over a median of 3 or 10 years of follow‐up (P > 0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Although not statistically significant, lower levels of 25(OH)D were suggestive of an association with increased dementia risk [hazard ratio for lowest versus highest race‐specific tertile: whites 1.32 (95% confidence interval 0.69, 2.55); blacks 1.53 (95% confidence interval 0.84, 2.79)].ConclusionsIn contrast to prior studies performed in older white populations, our study of late middle age white and black participants did not find significant associations between lower levels of 25(OH)D with lower cognitive test scores at baseline, change in scores over time or dementia risk.

Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus .