Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: 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.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

Characterisation of cytoplasmic uridyl transferases in yeast and human cells

Regulation of gene expression by terminal addition of uridyl residues to RNA substrates has recently emerged as a widespread phenomenon in eukaryotes. Studies in organisms ranging from fission yeast to human cells have shown that uridylation of RNA 3' ends stimulates rapid RNA degradation. However, many questions regarding the specificity of the uridyl transferases, the broad range of their substrates and the consequences of their loss are still unanswered. In light of this, the uridyl transferases Cid1 in Schizosaccharomyces pombe and ZCCHC11 in human cells and their roles in the regulation of gene expression were further characterised in this study. To begin with, the biochemistry of the Cid1 protein complex responsible for uridylation in Schizosaccharomyces pombe was analysed in more detail by mass spectrometry and in vitro assays. These experiments provided insights into the modulation of Cid1 activity by accessory factors. Next, the role of the human uridyl transferase ZCCHC11 in the regulation of replication- dependent histone mRNAs was examined. Results showed that ZCCHC11 is required for efficient destabilisation of histone mRNAs following inhibition or completion of DNA replication. In agreement with this finding, cDNA sequencing experiments showed that ZCCHC11-mediated uridylation is particularly prevalent at the end of S phase. Finally, this thesis also explored the phenotype resulting from ZCCHC11 knock-down with respect to the human cell cycle. Depletion of ZCCHC11 led to the occurrence of DNA damage and activation of the DNA integrity checkpoint, which in turn resulted in cell cycle delay. Taken together, the data presented in this thesis extend current knowledge of the uridyl transferases and their actions in fission yeast and human cells and provide a link between RNA regulation and cell cycle control

Characterisation of cytoplasmic uridyl transferases in yeast and human cells

Regulation of gene expression by terminal addition of uridyl residues to RNA substrates has recently emerged as a widespread phenomenon in eukaryotes. Studies in organisms ranging from fission yeast to human cells have shown that uridylation of RNA 3' ends stimulates rapid RNA degradation. However, many questions regarding the specificity of the uridyl transferases, the broad range of their substrates and the consequences of their loss are still unanswered. In light of this, the uridyl transferases Cid1 in Schizosaccharomyces pombe and ZCCHC11 in human cells and their roles in the regulation of gene expression were further characterised in this study. To begin with, the biochemistry of the Cid1 protein complex responsible for uridylation in Schizosaccharomyces pombe was analysed in more detail by mass spectrometry and in vitro assays. These experiments provided insights into the modulation of Cid1 activity by accessory factors. Next, the role of the human uridyl transferase ZCCHC11 in the regulation of replication- dependent histone mRNAs was examined. Results showed that ZCCHC11 is required for efficient destabilisation of histone mRNAs following inhibition or completion of DNA replication. In agreement with this finding, cDNA sequencing experiments showed that ZCCHC11-mediated uridylation is particularly prevalent at the end of S phase. Finally, this thesis also explored the phenotype resulting from ZCCHC11 knock-down with respect to the human cell cycle. Depletion of ZCCHC11 led to the occurrence of DNA damage and activation of the DNA integrity checkpoint, which in turn resulted in cell cycle delay. Taken together, the data presented in this thesis extend current knowledge of the uridyl transferases and their actions in fission yeast and human cells and provide a link between RNA regulation and cell cycle control.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The human cytoplasmic RNA terminal U-transferase ZCCHC11 targets histone mRNAs for degradation

Inhibition of eukaryotic DNA replication leads to the rapid suppression of histone synthesis, via 3′ uridylation of cytoplasmic histone mRNAs followed by their Lsm1–7-mediated decapping and degradation. Here we show that the human cytoplasmic RNA terminal U-transferase ZCCHC11, recently implicated in microRNA metabolism, associates with replication-dependent histone mRNAs. Knockdown of ZCCHC11 selectively blocked histone mRNA degradation following inhibition of DNA replication, whereas knockdown of PAPD1 or PAPD5, previously proposed as candidate histone mRNA U-transferases, had no such effect. Furthermore, a reduction in the proportion of histone transcripts that were uridylated was observed following ZCCHC11 knockdown. Our data indicate that ZCCHC11 is the terminal U-transferase responsible for targeting human histone mRNAs for degradation following inhibition or completion of DNA replication

The Impact of Atypical Sensory Processing on Adaptive Functioning and Maladaptive Behaviors in Autism Spectrum Disorder During Childhood: Results From the ELENA Cohort.

International audienceAtypical sensory processing is common in autism spectrum disorders (ASD), but their role in adaptive difficulties and problem behaviors is poorly understood. Our aim was to determine the prevalence and type of atypical sensory processing in children with ASD and investigate its impact on their adaptive functioning and maladaptive behaviors. We studied a subsample of 197 children rigorously diagnosed with ASD from the ELENA cohort. Children were divided into atypical and typical sensory processing groups and several independent variables were compared, including adaptive functioning and maladaptive behaviors. Overall, 86.8% of the children had at least one atypical sensory pattern and all sensory modalities were disturbed. Atypical sensory processing explained a significant part of the variance of behavioral problems

Translational research on cognitive and behavioural disorders in neurological and psychiatric diseases

International audienc