Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and ...31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in ...the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
With limited funding and biological specimen availability, choosing an optimal sampling design to maximize power for detecting gene-by-environment (G-E) interactions is critical. Exposure-enriched ...sampling is often used to select subjects with rare exposures for genotyping to enhance power for tests of G-E effects. However, exposure misclassification (MC) combined with biased sampling can affect characteristics of tests for G-E interaction and joint tests for marginal association and G-E interaction. Here, we characterize the impact of exposurebiased sampling under conditions of perfect exposure information and exposure MC on properties of several methods for conducting inference. We assess the Type I error, power, bias, and mean squared error properties of case-only, case-control, and empirical Bayes methods for testing/estimating G-E interaction and a joint test for marginal G (or E) effect and G-E interaction across three biased sampling schemes. Properties are evaluated via empirical simulation studies. With perfect exposure information, exposure-enriched sampling schemes enhance power as compared to random selection of subjects irrespective of exposure prevalence but yield bias in estimation of the G-E interaction and marginal E parameters. Exposure MC modifies the relative performance of sampling designs when compared to the case of perfect exposure information. Those conducting G-E interaction studies should be aware of exposure MC properties and the prevalence of exposure when choosing an ideal sampling scheme and method for characterizing G-E interactions and joint effects.
Neurobehavioral problems after chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL) have been a recent focus of investigation. This study extended previous research that suggested ...oxidative stress as a potential mechanism for chemotherapy-induced central nervous system injury by examining early markers of oxidative stress in relation to subsequent neurobehavioral problems. Oxidized and unoxidized components of phosphatidylcholine (PC) were measured in the cerebrospinal fluid of 87 children with ALL at diagnosis, induction, and consolidation. Behavioral assessments were conducted postconsolidation and at the end of chemotherapy. Results revealed a significant association between physiologic reactivity (high vs. low PC changes from diagnosis) and behavioral outcomes (high vs. low pathology). Elevated oxidized PC fraction change was predictive of increased problems with aggression at the end of therapy as well as postconsolidation adaptability. Furthermore, symptoms of hyperactivity systematically changed over time in relation to both unoxidized PC and oxidized PC fraction reactivity. These findings suggest that symptoms of behavioral problems occur early in the course of chemotherapy and that increases in the cerebrospinal fluid PC markers of oxidative stress during induction and consolidation may help to predict certain future behavioral problems.
Abstract
MicroRNAs (miRNAs) act as key post-transcriptional regulators of gene expression via binding to the 3’ untranslated regions (UTRs) of mRNAs. Single nucleotide polymorphisms (SNPs) found in ...the miRNA sequence and/or corresponding binding sites can affect the fidelity of this interaction, and evidence from candidate miRNA studies suggests that such SNPs may increase or decrease risk of tumor development. This study was designed to expand the search for miRNA-related polymorphisms important in cancer etiology across the genome and to investigate the association between thousands of genetic variants in miRNA target sites and colorectal cancer (CRC) risk using a novel genotyping platform, the Axiom® miRNA Target Site Genotyping Array (237,858 markers). The final study sample after quality control filtering included 605 cases and 615 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study of incident CRC cases in a geographically-defined area of northern Israel. The marginal association between each marker with minor allele frequency >=1% and CRC risk was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and the first two principal components (PC) to capture fine-scale population structure. There were 11 markers with p-values less than 3E-4, and the most statistically significant association involved rs12130051 (chr1:19545053; 3’-UTR of KIAA0090) with an OR of 2.24 (1.52,3.31) and p=4.48E-5. In addition, rs1051690 (chr5:142605172; 3’-UTR of ARHGAP26), was statistically significantly associated with decreased CRC risk (OR (95% CI): 0.71 (0.59, 0.85); p = 2.03E-4). Further, this study provided evidence for replication of a previously published locus, rs1051690 in the 3’UTR region of the insulin receptor gene, INSR (OR (95% CI): 1.27 (0.96,1.67); p = 0.09). A fixed-effects meta-analysis of sample-size weighted p-values from a recent publication in Carcinogenesis describing the INSR variant (Landi et al., 2012) and from the current MECC study yielded a combined p-value of 0.01. To our knowledge, this is the first study to examine the association between genetic variation in miRNA target sites and cancer risk using a genome-wide approach. Work is ongoing to replicate findings from this study and to characterize the functional impact of prioritized polymorphisms.
Citation Format: Stephanie L. Stenzel, Jeremy Gollub, Michael Shapero, Andrea Finn, Gad Rennert, Stephen B. Gruber. MicroRNA target site polymorphisms and colorectal cancer risk in the Ashkenazi Jewish population. 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 2560. doi:10.1158/1538-7445.AM2013-2560
Microsatellite Instability (MSI) is displayed approximately by 15% of colorectal cancers (CRC). Defective DNA mismatch repair (MMR) generates mutations at repetitive DNA sequences such as those ...located in the double strand break (DSB) repair gene
MRE11
. We assessed the mutational status of
MRE11
in a panel of 17 CRC cell lines and 46 primary tumors finding a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in
MRE11
may sensitize CRC cells to PARP-1 inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in
MRE11
compared to both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between
MRE11
expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R
2
=0.915, P<0.001). Using two experimental approaches, including shRNA knocking down
MRE11
in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant
MRE11
, we experimentally tried to confirm the role of
MRE11
in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in
MRE11
show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
Conservation of migratory species requires anticipating the potential impacts of extreme climatic events, such as extreme drought. During drought, reduced habitat availability for shorebirds creates ...the potential for changes in their abundance and distribution, in part because many species are highly mobile and rely on networks of interior and coastal habitats. Understanding how shorebirds responded to a recent drought cycle that peaked from 2013 to 2015 in central California, USA, will help optimize management of wetlands and fresh water for wildlife. In the Central Valley, a vast interior region that is characterized by a mosaic of wetlands and agricultural lands, we found 22% and 29% decreases in the annual abundance of shorebirds during periods of 3-year drought (2013-2015) and 2-year extreme drought (2014-2015), respectively, when compared to non-drought years. Lower abundance of shorebirds coincided with significant decreases in the mean proportion flooded of survey units (7% and 9%, respectively) that were reliant on fresh water. Drought was associated with lower abundance within both the interior Central Valley and coastal San Francisco Bay for greater and lesser yellowlegs (Tringa melanoleuca and T. flavipes) and long- and short-billed dowitchers (Limnodromus scolopaceus and L. griseus). Only dunlins (Calidris alpina) had patterns of abundance that suggested substantial shifts in distribution between the Central Valley and coastal regions of San Francisco Bay and Point Reyes. Our results indicate that drought has the potential to reduce, at least temporally, shorebird populations and flooded habitat in the Central Valley, and the ability to respond to drought by taking advantage of nearby coastal habitats may limit the long-term effects of drought on some species. Successful conservation strategies must balance the impacts of reduced habitat availability at interior sites with the ability of some migratory shorebirds to adapt rapidly to shifting distributions of resources.
To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic ...encephalopathy (HIE).
Secondary analysis of the
igh-dose
rythropoietin for
sphyxia and Encepha
opathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves.
Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA.
479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE).
Standardised SE was used across sites before and after TH. All providers underwent standardised SE training.
Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months.
Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe.
Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.
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