Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

Item does not contain fulltextBACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers

"Genuine" Casein Kinase: The False Sister of CK2 That Phosphorylates Secreted Proteins at S-X-E/pS Motifs

The early discovery of protein kinase CK2 (an acronym derived from \u201ccasein kinase 2\u201d) in 1954 was made possible by its ability to readily phosphorylate in vitro casein. For a while CK2 was suspected to be itself a bonafide casein kinase, because it proved able to re-phosphorylate the same residues which are phosphorylated in native casein. Later, however it was shown that, albeit similar and sometimes overlapping, the consensus sequences of CK2 and the genuine casein kinase isolated from the Golgi apparatus of the lactating mammary gland (G-CK) were definitely distinct (S/T-x-x-E/D/pS vs. S-x-E/pS). While CK2 was recognized as one of the most pleiotropic members of the big family of eukaryotic protein kinases (the so-called kinome) and has been implicated in several global diseases, with special reference to neoplasia, G-CK remained for decades an orphan enzyme, believed to play a dedicated but unexciting role in the biosynthesis of dairy proteins. Even though it became later evident that G-CK is also present in the Golgi apparatus of many tissues and is responsible for the phosphorylation of secreted proteins at S-x-E/pS motifs, its identity remained a mystery until 2012, when it was shown to be indistinguishable from Fam20C, a member of the four-jointed (FJ) atypical kinase family, causative of the Raine syndrome and other biomineralization disorders. Now we know that G-CK/Fam20C is as pleiotropic as CK2, being responsible for the generation of the largest proportion of the phosphosecretome, and, similar to CK2, it may represent a valuable druggable target. \ua9 Springer International Publishing Switzerland 2015

Increased prevalence of depression and anxiety in patients with migraine and interictal photophobia

BACKGROUND: Most patients with migraine report photophobia associated with headache; a subset report interictal photophobia. These patients are light sensitive even during headache-free periods. The objective of this case–control study was to assess the prevalence of symptoms of anxiety and depression in migraine patients with and without interictal photophobia. METHODS: We recruited 16 subjects with migraine and interictal photophobia, 16 age- and gender-matched migraine subjects without interictal photophobia, and 16 age- and gender- matched controls. Migraine subjects met International Headache Society classification criteria. Participants completed a photophobia questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Chi-square analyses and two-tailed Wilcoxon rank sum tests were used for the analyses. RESULTS: Subjects with interictal photophobia had significantly higher scores on the photophobia questionnaire compared to subjects without interictal photophobia. Subjects with interictal photophobia had significantly higher scores on the BDI-II and BAI compared to subjects without interictal photophobia. CONCLUSIONS: Migraine patients with interictal photophobia are more likely to manifest symptoms of depression and anxiety compared to migraine patients without interictal photophobia. Care providers should be aware of increased prevalence of these symptoms in this population and consider appropriate referrals. Future research could assess whether treatment of photophobia leads to improvements in symptoms of depression and anxiety in migraine patients