Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases

Optimal timing of influenza vaccine during pregnancy: A systematic review and meta-analysis

BACKGROUND: Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus. OBJECTIVES: To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns. METHODS: Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre-vaccination and within one month post-vaccination, post-vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random-effect meta-analyses and qualitative methods. RESULTS: Sixteen studies met the inclusion criteria. Meta-analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33- to 1.96-fold) and higher HI titres in cord/newborn blood (1.21- to 1.64-fold). CONCLUSIONS: This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women

O papel da Consciência Fonológica na leitura contextual medida pelo teste de Cloze The role of phonological awareness in contextual reading measured by the Cloze task

Estudos que investigam o papel das habilidades metalingüísticas na leitura demonstram que a habilidade de refletir sobre os sons da fala, a consciência fonológica, contribui para leitura de palavras isoladas e compreensão de texto. Considerando a importância do tema, esta pesquisa foi realizada com o objetivo de explorar as relações entre a consciência fonológica e a compreensão em leitura. Participaram 19 crianças da 1ª série e 23 da 2ª série, cujas médias de idade foram respectivamente, 87,5 meses (DP = 3,93) e 98,3 meses (DP = 4,58). Os resultados mostraram que os escores nas tarefas de consciência fonológica se associaram aos escores do teste de Cloze, utilizado como medida da compreensão em leitura. Os resultados são discutidos à luz das teorias sobre aquisição da leitura e sugere-se a realização de novas pesquisas.<br>Studies that investigate the role of metalinguistic abilities in reading show that the ability to reflect upon word's sound, phonological awareness, contributes to reading single words and reading comprehension. Considering the importance of this theme, this research was carried out with the objective of exploring the crelationship between phonological awareness and reading comprehension. Nineteen children from 1st grade and 23 from 2nd grade, whose mean ages were 87,5 months (SD = 3,93) and 98,3 months (SD = 4,58) participated in the study. The results show that the scores on the phonological awareness tasks were associated to the Cloze's score, used as a reading comprehension measure. The results are discussed on the light of the theories of reading acquisition