Citations

Background. Appropriate recommendations for a followup exam after an index colonoscopy are an important quality indicator. Lack of knowledge of polyp pathology at the time of colonoscopy may be one reason that followup recommendations are not made. Aim. To describe and compare the accuracy of followup recommendations made at colonoscopy based on the size and number of polyps with recommendations made at a later date based on actual polyp pathology. Methods. All patients who underwent screening and surveillance colonoscopy from March, 2012, to August, 2012, were included. Surveillance recommendations from the endoscopy reports were graded as “accurate” or “not accurate” based on the postpolypectomy surveillance guidelines established by US Multisociety Task Force on Colon Cancer. Polyp pathology was then used to regrade the surveillance recommendations. Results. Followup recommendations were accurate in 759/884 (86%) of the study colonoscopies, based upon size and number of polyps with the assumption that all polyps were adenomatous. After incorporating actual polyp pathology, 717/884 (81%) colonoscopies had accurate recommendations. Conclusion. In our practice, the knowledge of actual polyp pathology does not change the surveillance recommendations made at the time of colonoscopy in the majority of patients.

AbstractBackgroundLess is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non‐Hispanic whites.MethodsWhole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD‐related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC).ResultsForty‐four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African‐descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61).ConclusionsBecause AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.

Abstract Background. Transmembrane transport (GO:0055085) is the process whereby a solute/hormone/ion/iron is transported from one side of a membrane to the other. Disruption of these processes leads to defects in homeostasis which contributes to cancer risk. We hypothesized that germline single nucleotide polymorphisms (SNPs) in the cellular transport genes are associated with EOC risk and histopathology subtype. Methods. We genotyped 305 SNPs from 120 cellular transport related genes in 14,525 cases and 23,448 controls of European ancestry, 387 African, and 2,388 Asian ancestries from 43 studies in the Ovarian Cancer Association Consortium (OCAC). A custom Illumina iSelect designed for the Collaborative Oncological Gene-environment Study (COGS) was used. For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous (n=8,369), mucinous (n=943), endometroid (n=2,067) and clear cell (n=1,024) carcinoma) were analyzed, while for women of African and Asian ancestry only the serous subtype was analyzed adjusting for study site and first 5 principal components. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. We fitted a log-additive genetic model. Results. In women of European ancestry, the strongest evidence of an association for all invasive EOCs was the iron transport gene, HEPH rs17216603 (OR=0.85, 95%CI=0.78-0.93, P=2.8x10−4), which was also the most significant association for serous histological subtype (OR=0.81, 95%CI=0.73-0.91, P=2.0x10−4). For endometrioid EOC, the strongest association was observed in the glucuronidation gene, UGT1A5 rs11563251 (OR=0.82, 95%CI=0.73-0.92, P=6.6x10−4). For clear cell and mucinous EOC, the thyroid hormone transport protein, SERPINA7 rs1804495 showed the strongest associations (OR=1.06, 95%CI=1.06-1.38, P=0.0041) and (OR=0.85, 95%CI=0.73-0.98, P=0.0407), respectively. For women of African ancestry, the strongest association for serous EOC was the glutathione conjugation gene, MGST rs6488840 (OR=0.55, 95%CI=0.37-0.82, P=0.0035). This SNP was not significant in women of European or Asian ancestry. In women of Asian ancestry, the HEPH rs17216603 (OR=1.45, 95%CI=1.15-1.83, P=0.0019) demonstrated the strongest association, although the directionality of risk was reversed compared to European women. Conclusions. Our results suggest that variation in transmembrane transport genes may influence EOC risk and histopathologic subtype in women of European, African and Asian ancestries, highlighting the differences in the disease etiology across populations. Additional epidemiological and functional studies are warranted to elucidate translational and clinical utility of these associations. Citation Format: Ganna Chornokur, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Chen Zhihua, Ya-Yu Tsai, Ellen L. Goode, Julie M. Cunningham, Edwin Iversen, Susan J. Ramus, Andrew Berchuk, Joellen M. Schildkraut, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Paul Pharoah, Thomas A. Sellers, Catherine M. Phelan. Variation in transmembrane transport genes influence epithelial ovarian cancer risk and histopathologic subtype. [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 3644. doi:10.1158/1538-7445.AM2013-3644

Abstract Introduction The epithelial-mesenchymal transition (EMT) pathway contributes to epithelial ovarian cancer (EOC) progression. Previously we identified associations of single nucleotide polymorphisms (SNPs) in EMT-related genes and EOC risk (data not shown). To further investigate the role of EMT-related gene variants in EOC and to derive more reliable risk estimates, we evaluated associations for 795 SNPs from 278 EMT-related genes in a replication study of 43 studies within the Ovarian Cancer Association Consortium (OCAC). Methods The study population included 14,736 cases and 23,448 controls of European ancestry, 89 cases and 200 controls of African ancestry, and 249 cases and 1574 controls of Asian ancestry. The 795 SNPs were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, while for women of African and Asian ancestries only the serous subtype was analyzed. SNP analyses were conducted using unconditional logistic regression under a log-additive model separately for women of each ancestry. All analyses were adjusted for study site and population substructure within each ancestry. Results For women of European ancestry, the strongest evidence of an association for invasive cancers combined was observed for IGF1R rs10794486 (OR=1.05, 95%CI=1.02-1.09, P=0.002), which was also associated with serous (P=0.019), but not the other histological subtypes. In the histological subtype-specific analysis, the most significant association for serous was observed at NRP2 rs3771044 (OR=1.09, 95%CI=1.03-1.15, P=0.00014), for endometroid at rs1770247 (13q31.3, OR=1.16, 95%CI=1.07-1.25, P=0.00028), for clear cell at rs4848300 (2q13, OR=0.84, 95%CI=0.76-0.93, P=0.00099) and for mucinous at SEMA4B rs8030039 (OR=1.09, 95%CI=1.01-1.17, P=0.00019). For women of African ancestry, the strongest association for serous histological subtype was observed at F9 rs6048 (OR=1.71, 95%CI=1.17-2.50, P=0.006). This SNP was not significant in women of European or Asian ancestry. The strongest association for women of Asian ancestry was IGF1R rs10794486 (OR=1.68, 95%CI=1.16-2.45, P=0.007), which was also significant in women of European, but not African, ancestry. Conclusion Findings from this large study provide additional evidence that variants in EMT-related genes may be associated with ovarian cancer risk and that EMT susceptibility loci may differ by ovarian cancer histological subtypes. Furthermore, the findings suggest that susceptibility locus for the serous subtype may be different for women of African ancestry. Future studies are warranted to confirm these findings. Citation Format: Ernest K. Amankwah, Jonathan Tyrer, Hui-Yi Lin, Ya-Yu Tsai, Zhihua Chen, Gang Han, Xiaotao Qu, Ellen Goode, Julie Cunninghan, Edward Iverson, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven Narod, Paul Pharoah, Thomas A. Sellers, Catherine Phelan. Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry. [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 1352. doi:10.1158/1538-7445.AM2013-1352

Abstract The gene KDM6A/UTX was recently identified as a putative tumor suppressor (van Haaften et al). The gene is frequently lost in a variety of malignancies but most commonly in esophageal squamous cell carcinomas (8%) and multiple myeloma (10%). The initial characterization of UTX abnormalities in multiple myeloma utilized a mixture of 58 cell lines and patient samples. To establish the frequency of UTX inactivation in multiple myeloma we studied the copy number profiling dataset (n=239) available from the Multiple Myeloma Genomics Initiative (MMGI) and our internal dataset of 68 human myeloma cell lines which were characterized by array-based CGH (Agilent 400k), whole exome sequencing, and mRNA sequencing. We identified homozygous deletions in 2.5% of patients and 26.5% of cell lines. There are no mutations in the available whole genome and exome sequencing data from 38 patients in the MMGI that partially overlaps the 239 copy number samples sequencing. However, in the cell lines another 14.3% of samples showed loss of UTX through a variety of mechanisms (missense, nonsense, frameshifts, single exon deletions and insertions of LINE elements) detected by exome and mRNA sequencing, bringing the total percentage of cell lines with UTX inactivation to 40.8%. The increased frequency of UTX inactivation in cell lines likely suggests that it is associated with a more aggressive disease or promotes the growth of the tumor outside of the normal bone marrow microenvironment. As part of the cell line characterization phase of the project we found that ARD has a homozygous deletion encompassing the entire UTX locus while its isogenic counterparts, ARP-1 and CAG, express wild-type UTX at a level comparable to other cell lines without UTX abnormalities. To ensure these isogenic cell lines represent the same tumor not different tumors from the same individual we cloned the immunoglobulin receptor rearrangements in all there lines, which confirmed these are derived from the same original tumor. To develop this model system we first generated single cell clones from each of the three cell lines. Six clones from each were randomly selected and their DNA content was determined by flow cytometry. In all cases the clones matched the parental population in ploidy (ARD 3.2N, ARP 3.3N, CAG 3.8N). We randomly select one subclone from each cell line to characterize in detail using spectral karyotyping, array-based CGH, whole exome sequencing, mRNA sequencing, and CHIP-seq for H3K4me3, H3K27ac, H3K27me1, H3K27me2, and H3K27me3. The detailed characterization of this isogenic model system will make it an excellent platform for future work aimed at understanding how UTX loss contributes to myelomagenesis. Citation Format: Kristi Allen, Venkata Yellapantula, Quan Zhao, David Edwards, Marta Chesi, Leif Bergsagel, John Carpten, Jonathan Keats. Characterization of an isogenic model system for KDM6A/UTX loss in multiple myeloma. [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 5209. doi:10.1158/1538-7445.AM2013-5209

Abstract Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk. Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure. Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x10−3), rs2513927 (OR=1.05 p=6.1x10−3), rs2511703 (OR=1.05 p=9.8x10−3), rs3191333 (OR=1.05, p=1.5x10−2) and NPAS2 rs13012930 (OR=.95, p=3.5x10−2). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x10−2) and rs7117836 (OR=1.2, p=4.6x10−2), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x10−2), rs1026071 (OR=.89, p=1.8x10−2), and rs3816360 (OR=.91, p=4.8x10−2) and KLF10 rs2388232 (OR=1.1, p=3.3x10−2). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x10−3), rs3191333 (OR=1.04, p=1.4x10−2), rs2513927 (OR=1.04, p=1.9x10−2), and rs2511703 (OR=1.03, p=2.8x10−2). Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication. Funding: R01 CA149429 Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [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 4850. doi:10.1158/1538-7445.AM2013-4850 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and recur, invading brain tissue. Impaired response to treatment occurs rapidly conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance and spread in order to develop targeted therapies to combat this refractory setting. Our lab has previously published a role for the TWEAK-Fn14 ligand-receptor system in GB cell invasiveness and survival. Here we report that SGEF, a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and we hypothesize that SGEF plays an important role in promoting TWEAK-Fn14 mediated glioma invasion and survival. We show that upon TWEAK binding to Fn14, SGEF is recruited to the Fn14 cytoplasmic tail. The Fn14-SGEF interaction requires TRAF2 recruitment and leads to activation of Rac1. Importantly, SGEF mRNA expression is elevated in TMZ-resistant primary GB tumor grafts compared to those with known TMZ sensitivity. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-κB dependent manner and inhibition of SGEF expression via shRNA shutdown sensitizes glioma cells to TMZ-induced apoptosis and impairs colony formation following TMZ insult. Furthermore, gene expression analysis of SGEF depleted GB cells revealed impaired expression of a network of DNA repair and survival genes including ATM, ATR, BRCA2, and XIAP among others, as well as increased expression of the pro-apoptotic gene BAD. Understanding the role of SGEF in promoting chemotherapeutic resistance may direct the development of novel targeted therapeutics for TMZ refractory, invasive GB cells. Citation Format: Shannon P. Fortin, Ian T. Mathews, Jonathan Rollo, Julianna T.D. Ross, Marc H. Symons, Jann N. Sarkaria, Nhan L. Tran. SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival. [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 4108. doi:10.1158/1538-7445.AM2013-4108