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

Plant sugar signaling

In plants, sugars are not merely a carbohydrate metabolite or a photoassimilate of photosynthesis. They also play an important role in the intricate machinery of signal transduction. Sugar signaling is part of an ancient system for cellular adjustment to shifting environments and has been found to be crucial in responses to various stimuli, most importantly to the carbohydrate status of the plant. Gene responses to a changing carbohydrate status can vary greatly between plants and plant tissues. In general, carbohydrate depletion upregulates genes for photosynthesis, reserve mobilization and export processes, while high carbohydrate levels induce genes involved in storage or growth. Starch is the major storage compound in many plants and, hence, regulation of starch synthesis is to a large extent mediated via sugar signaling. Our aim in this project was to investigate regulators of carbohydrate metabolism in barley, sorghum and the model plant Arabidopsis thaliana. In barley, two highly similar and novel transcription factors, SUSIBA1 and SUSIBA2, were isolated and studied for their involvement in the regulation of two fructan synthesis genes, 6-SFT and 1-SST, and two starch synthesis genes ISO1 and SBEIIB. SUSIBA2 was found to bind as an activator to the promoter of the ISO1 and SBEIIB genes. Regulation of of SBEIIB also depended on binding of an unknown transcription factor to an element in the second intron. SUSIBA1 serves as a repressor and binds to the promoter of the 6-SFT and 1-SST genes. By the use of T-DNA insertion mutants we found two new sugar-inducible genes, AtWRKY4 and AtWRKY34, involved in the regulation of three different isoamylase genes in Arabidopsis. The AtWRKY4 and AtWRKY34 genes were also involved in the regulation of a nucleoside diphosphate kinase, NDPK3a. Both the two SUSIBAs, and AtWRKY4 and AtWRKY34, belong to group I of the WRKY family of transcription factors. These transcription factors display sequence similarities and bind to the same promoter element, the W-box. However, despite sequence similarities between the SUSIBAs, AtWRKY4 and AtWRKY34, they show diversity in function, which illustrates the complexity of sugar signaling in plants