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Sökning: WFRF:(Terry Kathryn L.)

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1.
  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
2.
  • Hollestelle, Antoinette, et al. (författare)
  • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
  • 2016
  • Ingår i: Gynecologic Oncology. - Academic Press. - 0090-8258. ; 141:2, s. 386-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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3.
  • Bojesen, Stig E., et al. (författare)
  • Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
  • 2013
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1546-1718. ; 45:4, s. 371-384
  • Tidskriftsartikel (refereegranskat)abstract
    • TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
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4.
  • Meeks, Huong D., et al. (författare)
  • BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
  • 2016
  • Ingår i: Journal of the National Cancer Institute. - Oxford University Press. - 0027-8874. ; 108:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
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5.
  • Phelan, Catherine M, et al. (författare)
  • Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.
  • 2017
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 49:5, s. 680-691
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
6.
  • Michailidou, Kyriaki, et al. (författare)
  • Association analysis identifies 65 new breast cancer risk loci
  • 2017
  • Ingår i: Nature. - 1476-4687. ; 551:7678, s. 92-
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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7.
  • Block, Keith I., et al. (författare)
  • Designing a broad-spectrum integrative approach for cancer prevention and treatment
  • 2015
  • Ingår i: Seminars in Cancer Biology. - Academic Press. - 1044-579X. ; 35, s. S276-S304
  • Forskningsöversikt (övrigt vetenskapligt)abstract
    • Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
8.
  • Brownstein, Catherine A., et al. (författare)
  • An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
  • 2014
  • Ingår i: Genome Biology. - 1465-6906. ; 15:3, s. R53
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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9.
  • Blois, Jessica L., et al. (författare)
  • A framework for evaluating the influence of climate, dispersal limitation, and biotic interactions using fossil pollen associations across the late Quaternary
  • 2014
  • Ingår i: Ecography. - Wiley-Blackwell. - 1600-0587. ; 37:11, s. 1095-1108
  • Tidskriftsartikel (refereegranskat)abstract
    • Environmental conditions, dispersal lags, and interactions among species are major factors structuring communities through time and across space. Ecologists have emphasized the importance of biotic interactions in determining local patterns of species association. In contrast, abiotic limits, dispersal limitation, and historical factors have commonly been invoked to explain community structure patterns at larger spatiotemporal scales, such as the appearance of late Pleistocene no-analog communities or latitudinal gradients of species richness in both modern and fossil assemblages. Quantifying the relative influence of these processes on species co-occurrence patterns is not straightforward. We provide a framework for assessing causes of species associations by combining a null-model analysis of co-occurrence with additional analyses of climatic differences and spatial pattern for pairs of pollen taxa that are significantly associated across geographic space. We tested this framework with data on associations among 106 fossil pollen taxa and paleoclimate simulations from eastern North America across the late Quaternary. The number and proportion of significantly associated taxon pairs increased over time, but only 449 of 56 194 taxon pairs were significantly different from random. Within this significant subset of pollen taxa, biotic interactions were rarely the exclusive cause of associations. Instead, climatic or spatial differences among sites were most frequently associated with significant patterns of taxon association. Most taxon pairs that exhibited co-occurrence patterns indicative of biotic interactions at one time did not exhibit significant associations at other times. Evidence for environmental filtering and dispersal limitation was weakest for aggregated pairs between 16 and 11 kyr BP, suggesting enhanced importance of positive species interactions during this interval. The framework can thus be used to identify species associations that may reflect biotic interactions because these associations are not tied to environmental or spatial differences. Furthermore, temporally repeated analyses of spatial associations can reveal whether such associations persist through time.
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10.
  • Cramer, Daniel W., et al. (författare)
  • Anti-CA15.3 and Anti-CA125 Antibodies and ovarian cancer risk : Results from the EPIC cohort
  • 2018
  • Ingår i: Cancer Epidemiology Biomarkers and Prevention. - American Association for Cancer Research. - 1055-9965. ; 27:7, s. 790-804
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined. Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression. Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both. Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types. Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC.
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