Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

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

A BAC Transgene Expressing Human CFTR under Control of Its Regulatory Elements Rescues Cftr Knockout Mice

Small-molecule modulators of cystic fibrosis transmembrane conductance regulator (CFTR) biology show promise in the treatment of cystic fibrosis (CF). A Cftr knockout (Cftr KO) mouse expressing mutants of human CFTR would advance in vivo testing of new modulators. A bacterial artificial chromosome (BAC) carrying the complete hCFTR gene including regulatory elements within 40.1 kb of DNA 5′ and 25 kb of DNA 3′ to the gene was used to generate founder mice expressing hCFTR. Whole genome sequencing indicated a single integration site on mouse chromosome 8 (8qB2) with ~6 gene copies. hCFTR+ offspring were bred to murine Cftr KO mice, producing hCFTR+/mCftr− (H+/m−) mice, which had normal survival, growth and goblet cell function as compared to wild-type (WT) mice. Expression studies showed hCFTR protein and transcripts in tissues typically expressing mCftr. Functionally, nasal potential difference and large intestinal short-circuit (Isc) responses to cAMP stimulation were similar in magnitude to WT mice, whereas small intestinal cAMP ΔIsc responses were reduced. A BAC transgenic mouse with functional hCFTR under control of its regulatory elements has been developed to enable the generation of mouse models of hCFTR mutations by gene editing for in vivo testing of new CF therapies. © 2019, The Author(s)

Functional compounds present in garlic cloves stored under refrigeration from crops in Brazil and China

O objetivo desta pesquisa foi determinar o teor de compostos funcionais presentes em bulbilhos de alho das cultivares 'Caçador' e 'Peruano', originárias do Brasil, e da cultivar 'Jinxiang', proveniente da China, durante o armazenamento pós-colheita até sessenta dias. O delineamento experimental utilizado foi o inteiramente casualizado, em esquema fatorial 3x5 (três cultivares de alho x 5 períodos de armazenagem), com três repetições, sendo a unidade experimental composta por 10 bulbos de alho. Os bulbos foram armazenados à temperatura de 22±1°C e umidade relativa de 70±2% e analisados quinzenalmente para teores de alicina, compostos fenólicos e atividade antioxidante pelo sistema -caroteno/ácido linoléio. De maneira geral, verificou-se que as propriedades funcionais das cultivares de alho estudadas foram alteradas durante o armazenamento. O perfil dos teores de alicina não foi alterado no período de armazenamento para a cultivar 'Caçador'. Entretanto, o perfil foi de degradação do bioativo aos 45 e 15 dias de armazenamento para as cultivares 'Peruano' e 'Jinxiang', respectivamente. O potencial antioxidante, medido pelo sistema -caroteno/ácido linoléico para as cultivares 'Caçador' e 'Jinxiang', foi superior em relação à cultivar 'Peruano', no início da avaliação. O perfil para todas as cultivares foi de redução do potencial, sendo que, a partir dos 30 dias de avaliação, deixou-se de observar essas diferenças. Quanto ao conteúdo de compostos fenólicos totais, observaram-se maiores teores para a cultivar 'Jinxiang' em relação às cultivares 'Caçador' e 'Peruano' no início da avaliação. Todas as cultivares apresentaram aumento significativo a partir dos 15 dias de avaliação. Portanto, as cultivares de alho avaliadas possuem atividade antioxidante, proveniente dos compostos organossulfurados e compostos fenólicos, a qual foi alterada com o armazenamento refrigerado.The objective of the present research was to determine the content of functional compounds in garlic cloves of two Brazilian cultivars ('Caçador' and 'Peruano') one Chinese cultivar ('Jinxiang'), during the postharvest storage up to 60 days. The experiments were carried out in a completely randomized design, in a factorial scheme 3x5 (3 cultivars; 5 samplings times) with 3 replicates. Experimental unit was comprised by 10 garlic bulbs. Garlic bulbs were stored at 22±1°C and 70±2% RH and analyzed, every 15 days for allicin, phenolic compounds and antioxidant activity using the -carotene/linoleic acid method. In general, it was observed that functional compounds were altered in the garlic cultivars studied. The profile of the levels of allicin was not changed during the period of storage for the variety 'Caçador'. However, the profile was of bioactive degradation at 45 and 15 days of storage for 'Peruano' and 'Jinxiang' cultivars, respectively. The antioxidant potential measured by the system ?-carotene/ linoleic acid for cultivars 'Caçador' and 'Jinxiang' were higher than the 'Peruano' cultivar, at the beginning of the evaluation. The profile for all cultivars was of reduction of potential, and after 30 days these differences were no observed. Regarding the content of phenolic compounds it was observed that 'Jinxiang' showed higher levels than in the cultivars 'Peruano' and 'Caçador', at the beginning of the evaluation. All cultivars showed a significant increase from 15 days evaluation. Therefore, the garlic cultivars evaluated had antioxidant activity of compounds derived from organosulfur and phenolic compounds, which was modified with storage under refrigeration