Citations

Abstract Pancreatic ductal adenocarcinoma (PDA) affects over 44,000 people in the United States every year and carries a dismal prognosis, with a 5-year survival rate of just 5%. A subset of these patients (5-10%) report a familial history of the disease. The genetic etiology in these familial cases is poorly defined, with known susceptibility genes, such as: BRCA2, PALB2, CDKN2A, BRCA1, PRSS1 and STK11, accounting for only 10-15% of familial pancreatic cancer. In an effort to identify previously unappreciated pancreatic cancer susceptibility genes, we used next generation sequencing technology to evaluate the whole genome and whole exome sequences of 16 (6 families) and 22 individuals (10 families) respectively. All of these families enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology (PacGene) Consortium, all had at least three members with PDA, and DNA was available from at least two affected members in each kindred. Using this approach, we identified heterozygous, inactivating, ATM mutations in two kindreds with familial pancreatic cancer (c.8266A>AT; p.K2756X and c.170G>GA; p.W57X). These mutations were previously reported as disease causing variants in patients with ataxia-telangiectasia, an autosomal recessive condition resulting from bi-allelic deleterious mutations of ATM. Interestingly, heterozygotes of deleterious ATM mutations have an increased risk of breast cancer. However, there have been no previous reports of deleterious ATM mutations in the germline of familial PDA patients. In our study, mutations segregated with disease in both kindreds and tumor analysis demonstrated Loss of heterozygosity (LOH) of the wild-type allele. Sequence analysis of the entire ATM gene in an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene (c.3214G>GT; p.E1072X, c.6095G>GA; p.R2032K, IVS41-1G>GT and c.3801delG), while no deleterious mutations were identified in 190 spouse controls (p=0.046). When considering only the mostly severely affected families, those with three or more pancreatic cancer cases, four deleterious mutations were found in 87 families (P=0.009). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition and have significant implications in the management of affected individuals and the risk assessment of family members. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2628. doi:1538-7445.AM2012-2628

Abstract MicroRNAs (miRNAs) play an important role in a variety of physiological processes as well as pathophysiological processes, including cancinogenesis. This study was to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to reveal individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues as compared to normal cervical epithelium. The expression of 12 miRNAs including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203 were significantly different between high-grade CIN and normal epithelium. This miRNA signature was further validated by an independent set of high-grade CIN tissue. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma (SCC) from normal controls. Target prediction analysis revealed that these dysregulated miRNAs control the apoptosis signaling pathway and cell cycle regulation. These findings contribute to understanding of the pathogenesis of cervical carcinoma at the molecular level. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5047. doi:1538-7445.AM2012-5047

Objective Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. Design Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ∼66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. Results GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. Conclusion Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

Abstract Some studies show that childbearing at older age is associated with lower risk of endometrial cancer, but whether the association is independent of number of children or other factors still requires clarification. We pooled individual-level data from epidemiologic studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Data on age at last birth and/or last pregnancy were available from 14 studies: 11 case-control studies and 3 cohort studies; the latter were analyzed using a nested case-control design. A total of 9,613 endometrial cancer cases and 17,112 controls were included in the analysis. The majority of women were White (82%) and older than 55 years (69%). We estimated the effects of age at last birth using data from 12 studies and age at last pregnancy using data from 10 studies on the risk of endometrial cancer by calculating odds ratios (OR) and 95% confidence intervals (95% CI) using logistic regression models. Potential confounders included in the analysis were race, body mass index, parity, age at menarche, age at first birth, oral contraceptive use, postmenopausal hormone use, smoking status, and report of diabetes. After adjusting for potential confounders, a reduction in endometrial cancer risk was observed in women with increasing age at last birth (P trend &lt;0.0001) and age at last pregnancy (P trend &lt;0.0001). The OR per five-year increase in age at last birth and age at last pregnancy was 0.90 (95%CI: 0.86, 0.94) and 0.91 (95% CI: 0.87, 0.95), respectively. Women who had their last child at an age &gt;40 years were at a 34% decreased risk compared with women who had their last child at an age &lt;25 years (95% CI: 0.52, 0.82). Compared to women with age at last pregnancy &lt;25 years, those with age at last pregnancy &gt;40 years had a 30% decreased risk of endometrial cancer (95%CI: 0.57, 0.86). Inverse associations were observed for Whites and Asians in race-specific analysis and also in analysis restricted to women with at least 2 births. In this large pooled analysis, we show that late age at last birth or last pregnancy is a strong and independent protective factor for endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1900. doi:10.1158/1538-7445.AM2011-1900

Abstract The etiology of ovarian cancer is poorly understood but there is clearly a heritable component. Efforts to identify susceptibility alleles rarely consider interactions among alleles or their joint effects because it quickly becomes computationally intractable. In this study, we sought to identify multi-SNP effects jointly with a pathway-based analysis (GSEA-SNP) of 1,952 EOC cases and 2,042 frequency-matched controls genotyped with the Illumina 610K array. All subjects were self-reported non-Hispanic non-Jewish Caucasians, with SNP and sample call rates &gt; 95%. Subjects with ambiguous gender, unresolved identical genotypes and &lt; 80% European ancestry were excluded. SNPs with MAF &lt; 1% were excluded. Missing genotypes were inferred using Mach based on the HapMap CEU population. SNPs not within introns were annotated to genes within 100 bp. We retrieved the following databases of gene sets (GSs) from a compiled database, MsigDB: human chromosome and cytogenetic band, chemical and genetic perturbations, canonical pathways, microRNA binding targets, transcription factor targets (TFT), cancer gene neighborhood (CGN), Cancer modules and Gene Ontology. The GSEA-SNP approach calculates and rank orders the trend statistic for association between each SNP and EOC risk. The Enrichment Score (ES) estimates the overrepresentation of top-ranked SNPs for each GS; the statistical significance was estimated using 10,000 permutations. The ES was normalized according to the size of GS to yield Normalized Enrichment Score (NES). The false discovery (FDR) rate was estimated using NES to adjust for multiple hypothesis testing. A total of 5181 gene-sets were included in the analysis. When controlling the FDR at 15%, 14 of the GSs were highly enriched with association signals, including two chromosomal regions, 8q13 (p = 0.0055, FDR = 0.15) and 6p24 (p = 0.0012, FDR = 0.08). BIOCARTA_LYM_PATHWAY, a pathway related to cell adhesion and diapedesis of lymphocytes, was also significant (p = 0.0002, FDR = 0.12). A TFT GS, composed of genes with promoter regions around transcription start sites containing the motif GGCNRNWCTTYS, was associated with risk (p = 0.0004, FDR = 0.08). Currently, no known transcription factors bind to this computationally predicted motif. Molecular function of double stranded RNA binding was also enriched (p = 0.005, FDR = 0.10). The remaining enriched sets were CGN sets, for which the neighborhoods around the cancer genes were originally defined using correlation of gene expression from 4 large data sets of various cancer types. The enriched CGN included: CD48 (p = 0.011), CD53 (p = 0.009), CD97 (p = 0.011), INPP5D (p = 0.010), PTPN6 (p = 0.008), VAV1 (p = 0.011), ITGAL (p = 0.012), PTPRC (p = 0.012), and STAT6 (p = 0.010). In summary, these analyses detected biologically plausible GSs related to etiology of EOC, highlighting SNPs in core enrichment groups that were not identified using individual SNP tests. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4729. doi:10.1158/1538-7445.AM2011-4729