Citations

Abstract Purpose: Clustering of breast and colorectal cancer has been observed within families in population-based studies giving rise to speculation that there are “breast-colon” cancer susceptibility genes. We performed a genome-wide association study (GWAS) to identify genetic markers associated with a potential breast-colon cancer phenotype. Methods: Cases and controls were ascertained from the Breast and Colon Cancer Family Registries’ (CFR) GWAS subjects. “Breast-colon phenotype” definition was based on 2 or more breast and colon cancer cases diagnosed in first- or second-degree relatives within a family. Cases (n = 985) were women with a history of breast cancer and a family history of colorectal cancer, or persons with colorectal cancer with a family history of breast cancer. Unrelated controls (n = 1769) were frequency matched to cases for age and gender. Following standard quality control measures, 6,220,060 directly measured and imputed single nucleotide polymorphisms (SNPs) were included in the discovery set. SNPs associated at p<1×10−5 were analyzed in a replication dataset of cases (n = 293) and controls (n = 2103) from the Genetics and Epidemiology of Colorectal Cancer Consortium. Results: In a regression model that included gender, age, CFR center and 6 principal components, the top association in the discovery set was in the chromosome 8q22.3 region overlying the BAALC gene (top SNP rs12548629, P = 3.63×10−7). In the replication dataset, of 341 SNPs tested, the top signal was found in multiple correlated SNPs overlying the ROBO1 gene on chromosome 3p12 (rs7429100, P = 2.8×10−3), however, the signal on chromosome 8, the BAALC gene did not replicate. In the discovery set, P values for the SNPs overlaying ROBO1 gene ranged from 2.2×10−5 to 9.7×10−5 (rs7429100, P = 3.9×10−5). The combined meta-analysis showed strongest association at the ROBO1 gene (rs7429100, Pfixed effects 1.84×10−6, Pheterogeneity >0.05 for testing for heterogeneity between the overall discovery set and the replication set). ROBO1 (roundabout, axon guidance receptor, homolog 1) is a transmembrane receptor of the immunoglobulin family and is differentially expressed in human cancers, with a possible role as a tumor suppressor gene. Low ROBO1 expression has been shown to be an adverse prognostic factor for invasive ductal breast cancer and may also play a role in pathogenesis of colorectal cancer. BAALC (brain and acute leukemia, cytoplasmic) is predominantly expressed by neural and blood cells and is largely implicated in acute leukemia. Conclusion: In this exploratory analysis, to elucidate genes/regions associated with pleiotropic effect for breast and colorectal cancer risk we identified germline variation in the region of ROBO1 and BAALC. Validation in a larger dataset and functional characterization of the loci is warranted to elucidate mechanisms by which these genes/SNPs may contribute to the development of breast and colorectal cancer. Citation Format: Mala Pande, Aron Joon, Sanjay Shete, Abenaa M. Brewster, Cathy Eng, Wei V. Chen, Habibul Ahsan, Irene L. Andrulis, Esther M. John, Yi Lin, Polly A. Newcomb, Noralane M. Lindor, Christopher I. Amos, John Hopper, Patrick M. Lynch. Risk loci for a breast-colon cancer phenotype: results from a genome-wide association study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2015-2782

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: Parkinson’s disease (PD) patients with 20 years or more survival (PD-20) are not well characterized. Objective: To evaluate PD-20 patient characteristics and identify areas for improvement of their health care. Methods: The international, multicenter National Parkinson’s Foundation Quality Improvement Initiative (NPF-QII) study database was queried to identify PD-20 subjects. Demographic and clinical data were analyzed. Results: We identified 187 PD-20 subjects (55% men) representing 4% (187/4,619) of all NPF-QII participants. Subjects were mean age 69.5 years; mean age at PD onset was 44.0 years. The majority (75%) had 20-25 years of PD duration, the longest duration being 49 years. They were median Hoehn and Yahr stage 3, and 75% had motor fluctuations. Half (54%) reported exercising. The majority (89%) were living at home and required a caregiver (88%). They were mildly cognitively impaired for age (Montreal Cognitive Assessment estimate 22.6±3.7), with most deficits in verbal fluency and delayed recall. Quality of life (Parkinson’s Disease Quality of Life Questionnaire index 36±15%) was mild to moderately impaired, with most impairment in mobility and activities of daily living. Caregiver strain measured by the Multidimensional Caregiver Strain Index (27±16%), recorded highest subscores in social constraint. PD-20 subjects aged <70 years versus ≥70 only differed significantly by worse cognition ( P < 0.0001). Conclusions: PD-20 subjects reflect an elite group of PD survivors with early-onset disease and relatively mild cognitive disability despite long disease duration. Interventions for caregivers, mobility, and activities of daily living are areas that could improve caregiver burden and patient quality of life.

Abstract Background: Guidelines recommend germline mutation testing of breast cancer predisposition genes in triple negative (TN) breast cancer cases with a family history of breast or ovarian cancer or when diagnosed under age 60. However, the prevalence of mutations in these genes among TN cases unselected for family history of breast or ovarian cancer is not known. Methods: To assess the frequency of mutations in 16 predisposition genes in TN cases we screened a large cohort of TN patients (n=1824) unselected for family history of breast or ovarian cancer from 12 centers and 824 study matched unaffected controls for mutations using a panel-based sequencing approach. Results: Deleterious mutations were identified in 15% of TN patients: 8.5% had BRCA1, 2.7% had BRCA2, and 3.6% had mutations in 12 other genes. Mutations in non-BRCA1/2 genes encoding proteins implicated in homologous recombination repair of DNA double strand breaks were detected at the same frequency as in breast cancer families. TN cases with mutations had high-grade tumors and were diagnosed at an earlier age than non-mutated cases. However, 10% of TN cases diagnosed at ≥60 years and 5% with no family history of cancer were also found to carry mutations. Inactivating mutations in non-BRCA1/2 predisposition genes were associated with moderate to high risks of TN breast cancer. Conclusions: National Comprehensive Cancer Network (NCCN) guidelines support clinical genetic testing of breast cancer predisposition genes in 95% of TN breast cancer patients carrying mutations in susceptibility genes. In contrast, National Institute of Health and Care Excellence (NICE) guidelines in the U.K. do not support genetic testing of a substantial proportion of TN patients with predisposing alleles. Frequency tables for inherited mutations in known predisposition genes based on age of diagnosis and family history of cancer will allow for selection of TN patients most likely to carry mutations in the predisposition genes. Citation Format: Fergus J Couch, Steven N Hart, Priyanka Sharma, Amanda Ewart Toland, Penelope Miron, Janet E Olson, Andrew Godwin, Vernon S Pankratz, Curtis Olswold, Seth Slettedahl, Lucia Guidugli, Matthias W Beckmann, Brigitte Rack, Arif B Ekici, Irene Konstantopoulou, Florentia Fostira, George Fountzilas, Liisa M Pelttari, Song Yao, Judy Garber, Angela Cox, Hiltrud Brauch, Christine Ambrosone, Heli Nevanlinna, Drakoulis Yannoukakos, Susan L Slager, Celine M Vachon, Diana M Eccles, Peter A Fasching. Triple-negative breast cancer: Frequency of inherited mutations in breast cancer susceptibility genes [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 P4-12-03.

The mucosal gene expression in rectosigmoid mucosa (RSM) in irritable bowel syndrome with diarrhea (IBS-D) is unknown. Our objectives were, first, to study mRNA expression [by RT2 PCR of 19 genes pertaining to tight junctions, immune activation, intestinal ion transport and bile acid (BA) homeostasis] in RSM in IBS-D patients ( n = 47) and healthy controls ( n = 17) and study expression of a selected protein (PDZD3) in 10 IBS-D patients and 4 healthy controls; second, to assess RSM mRNA expression according to genotype and fecal BA excretion (high ≥2,337 μmol/48 h); and third, to determine whether genotype or mucosal mRNA expression is associated with colonic transit or BA parameters. Fold changes were corrected for false detection rate for 19 genes studied ( P < 0.00263). In RSM in IBS-D patients compared with controls, mRNA expression of GUC2AB, PDZD3, and PR2Y4 was increased, whereas CLDN1 and FN1 were decreased. One immune-related gene was upregulated (C4BP4) and one downregulated (CCL20). There was increased expression of a selected ion transport protein (PDZD3) on immunohistochemistry and Western blot in IBS-D compared with controls ( P = 0.02). There were no significant differences in mucosal mRNA in 20 IBS-D patients with high compared with 27 IBS-D patients with normal BA excretion. GPBAR1 ( P < 0.05) was associated with colonic transit. We concluded that mucosal ion transport mRNA (for several genes and PDZD3 protein) is upregulated and barrier protein mRNA downregulated in IBS-D compared with healthy controls, independent of genotype. There are no differences in gene expression in IBS-D with high compared with normal fecal BA excretion.

Unruptured intracranial aneurysms (UIAs) are a major public health issue. These lesions have become increasingly recognized in recent years with the advent of advanced cerebral imaging techniques. Epidemiological evidence from multiple sources suggests that most intracranial aneurysms do not rupture. Therefore, it is desirable to identify which UIAs are at greatest risk of rupture when considering which to repair. It is important to compare size-, site-, and group-specific natural history rates with size-, site-, and age-specific morbidity and mortality associated with UIA repair because increased natural history risk often is associated with increased risk of aneurysm repair. Patient age is crucial in decision making because of its major effect on operative morbidity and mortality; however, it does not substantially affect natural history. The effect of age is most notable in patients about 50 years of age and older for open surgery and about 70 years of age and older for endovascular procedures. In general, rupture risk is lowest for patients in asymptomatic group 1 (no history of subarachnoid hemorrhage) with UIAs less than 7 mm in diameter in the anterior circulation. Surgical morbidity and mortality are most favorable for asymptomatic patients younger than 50 years who have UIAs less than 24 mm in diameter in the anterior circulation and no history of ischemic cerebrovascular disease. Endovascular morbidity and mortality may be less age dependent, and this could favor endovascular procedures, particularly in patients aged 50 to 70 years. An important issue is determining immediate vs long-term risk regarding treatment effectiveness and durability. This issue emphasizes the importance of long-term follow-up in patients after surgical and endovascular procedures.

Abstract Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P &lt; 10−5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk. Cancer Res; 75(12); 2457–67. ©2015 AACR.