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  • 1
    Keywords: ASSOCIATION
    Abstract: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Type of Publication: Journal article published
    PubMed ID: 25336561
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  • 2
    Keywords: DISEASES ; SUSCEPTIBILITY ; VARIANTS ; OXIDATIVE STRESS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; OVARIAN ; CONSORTIUM ; MULTIPLE ; GENETIC MODIFIERS ; DNA HAPLOGROUPS
    Abstract: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
    Type of Publication: Journal article published
    PubMed ID: 25925750
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  • 3
    ISSN: 0167-2584
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2012-12-18
    Description: A widespread system used by bacteria for protection against potentially dangerous foreign DNA molecules consists of the clustered regularly interspaced short palindromic repeats (CRISPR) coupled with cas (CRISPR-associated) genes. Similar to RNA interference in eukaryotes, these CRISPR/Cas systems use small RNAs for sequence-specific detection and neutralization of invading genomes. Here we describe the first examples of genes that mediate the inhibition of a CRISPR/Cas system. Five distinct 'anti-CRISPR' genes were found in the genomes of bacteriophages infecting Pseudomonas aeruginosa. Mutation of the anti-CRISPR gene of a phage rendered it unable to infect bacteria with a functional CRISPR/Cas system, and the addition of the same gene to the genome of a CRISPR/Cas-targeted phage allowed it to evade the CRISPR/Cas system. Phage-encoded anti-CRISPR genes may represent a widespread mechanism for phages to overcome the highly prevalent CRISPR/Cas systems. The existence of anti-CRISPR genes presents new avenues for the elucidation of CRISPR/Cas functional mechanisms and provides new insight into the co-evolution of phages and bacteria.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bondy-Denomy, Joe -- Pawluk, April -- Maxwell, Karen L -- Davidson, Alan R -- MOP-6279/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jan 17;493(7432):429-32. doi: 10.1038/nature11723. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242138" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/*genetics ; Biological Evolution ; Gene Expression Regulation, Viral ; Genes, Bacterial/*genetics ; Genes, Viral/*genetics ; Genome, Viral/genetics ; Inverted Repeat Sequences/*genetics ; Molecular Sequence Data ; Pseudomonas aeruginosa/genetics/*immunology/*virology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2015-09-30
    Description: The battle for survival between bacteria and the viruses that infect them (phages) has led to the evolution of many bacterial defence systems and phage-encoded antagonists of these systems. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system that is one of the most widespread means by which bacteria defend themselves against phages. We identified the first examples of proteins produced by phages that inhibit a CRISPR-Cas system. Here we performed biochemical and in vivo investigations of three of these anti-CRISPR proteins, and show that each inhibits CRISPR-Cas activity through a distinct mechanism. Two block the DNA-binding activity of the CRISPR-Cas complex, yet do this by interacting with different protein subunits, and using steric or non-steric modes of inhibition. The third anti-CRISPR protein operates by binding to the Cas3 helicase-nuclease and preventing its recruitment to the DNA-bound CRISPR-Cas complex. In vivo, this anti-CRISPR can convert the CRISPR-Cas system into a transcriptional repressor, providing the first example-to our knowledge-of modulation of CRISPR-Cas activity by a protein interactor. The diverse sequences and mechanisms of action of these anti-CRISPR proteins imply an independent evolution, and foreshadow the existence of other means by which proteins may alter CRISPR-Cas function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bondy-Denomy, Joseph -- Garcia, Bianca -- Strum, Scott -- Du, Mingjian -- Rollins, MaryClare F -- Hidalgo-Reyes, Yurima -- Wiedenheft, Blake -- Maxwell, Karen L -- Davidson, Alan R -- MOP-130482/Canadian Institutes of Health Research/Canada -- MOP-136845/Canadian Institutes of Health Research/Canada -- P20GM103500/GM/NIGMS NIH HHS/ -- R01GM108888/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):136-9. doi: 10.1038/nature15254. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59717, USA. ; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416740" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*metabolism/*virology ; Bacteriophages/*metabolism ; CRISPR-Associated Proteins/*antagonists & inhibitors/metabolism ; CRISPR-Cas Systems/genetics/*physiology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; DNA Helicases/antagonists & inhibitors/metabolism ; DNA, Viral/metabolism ; DNA-Binding Proteins/antagonists & inhibitors/metabolism ; Endonucleases/antagonists & inhibitors/metabolism ; *Evolution, Molecular ; Protein Binding ; Protein Subunits/antagonists & inhibitors/metabolism ; Repressor Proteins/genetics/metabolism ; Substrate Specificity ; Viral Proteins/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2012-12-18
    Description: Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 x 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 x 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 x 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ruark, Elise -- Snape, Katie -- Humburg, Peter -- Loveday, Chey -- Bajrami, Ilirjana -- Brough, Rachel -- Rodrigues, Daniel Nava -- Renwick, Anthony -- Seal, Sheila -- Ramsay, Emma -- Duarte, Silvana Del Vecchio -- Rivas, Manuel A -- Warren-Perry, Margaret -- Zachariou, Anna -- Campion-Flora, Adriana -- Hanks, Sandra -- Murray, Anne -- Ansari Pour, Naser -- Douglas, Jenny -- Gregory, Lorna -- Rimmer, Andrew -- Walker, Neil M -- Yang, Tsun-Po -- Adlard, Julian W -- Barwell, Julian -- Berg, Jonathan -- Brady, Angela F -- Brewer, Carole -- Brice, Glen -- Chapman, Cyril -- Cook, Jackie -- Davidson, Rosemarie -- Donaldson, Alan -- Douglas, Fiona -- Eccles, Diana -- Evans, D Gareth -- Greenhalgh, Lynn -- Henderson, Alex -- Izatt, Louise -- Kumar, Ajith -- Lalloo, Fiona -- Miedzybrodzka, Zosia -- Morrison, Patrick J -- Paterson, Joan -- Porteous, Mary -- Rogers, Mark T -- Shanley, Susan -- Walker, Lisa -- Gore, Martin -- Houlston, Richard -- Brown, Matthew A -- Caufield, Mark J -- Deloukas, Panagiotis -- McCarthy, Mark I -- Todd, John A -- Breast and Ovarian Cancer Susceptibility Collaboration -- Wellcome Trust Case Control Consortium -- Turnbull, Clare -- Reis-Filho, Jorge S -- Ashworth, Alan -- Antoniou, Antonis C -- Lord, Christopher J -- Donnelly, Peter -- Rahman, Nazneen -- 068545/Z/02/Wellcome Trust/United Kingdom -- 083948/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 091157/Wellcome Trust/United Kingdom -- 095552/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- 11174/Cancer Research UK/United Kingdom -- C12292/A11174/Cancer Research UK/United Kingdom -- CZB/4/540/Chief Scientist Office/United Kingdom -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G0900747 91070/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- England -- Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics & Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242139" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Breast Neoplasms/*genetics ; Cluster Analysis ; Exons ; Female ; Genetic Predisposition to Disease/*genetics ; Humans ; Isoenzymes/genetics ; Lymphocytes/metabolism ; *Mosaicism ; *Mutation ; Ovarian Neoplasms/*genetics ; Phosphoprotein Phosphatases/*genetics ; Sequence Analysis, DNA ; Tumor Suppressor Protein p53/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Keywords: RECEPTOR ; CANCER ; DISEASE ; RISK ; GENE ; ALLELES ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM ; TUMOR SUBTYPES ; URIC-ACID NEPHROLITHIASIS
    Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 22351618
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  • 8
  • 9
  • 10
    Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 22253144
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