Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

BACKGROUND: BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not. METHODS: DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test. RESULTS: A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level. CONCLUSIONS: We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data

Chest imaging in cystic fibrosis studies: What counts, and can be counted?

Background: The dawn of precision medicine and CFTR modulators require more detailed assessment of lung structure in cystic fibrosis (CF) clinical studies. Various imaging markers have emerged and are measurable, but clarity is needed to identify what markers should count for clinical studies. High-resolution chest computed tomography (CT) scoring has yielded sensitive markers for the study of CF disease progression. Once completed, CT scores from ongoing randomized controlled trials can be used to examine relationships between imaging endpoints and therapeutic effectiveness. Similarly, Magnetic Resonance Imaging (MRI) is in development to generate structural as well as functional markers. Results: The aim of this review is to characterize the role of currently available CT and MRI markers in clinical studies, and to discuss study design, data processing and statistical challenges unique to these endpoints in CF studies. Suggestions to overcome these challenges in CF studies are included. Conclusions: To maximize the potential of CT and MRI markers in clinical studies and advance treatment of CF disease progression, efforts should be made to conduct longitudinal randomized controlled trials including these modalities, develop data repositories, promote standardization and conduct reproducible research

The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis

Introduction: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease. Methods: All patients aged <6 years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth–Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations. Results: 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09–0.54; p=0.007) but not infection (0.23, 95% CI −0.01–0.47; p=0.060) detections. Reference equations were determined. Conclusions: Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children

Impact of lung disease on respiratory impedance in young children with cystic fibrosis

This study aimed to evaluate the ability of the forced oscillation technique (FOT) to detect underlying lung disease in preschool children with cystic fibrosis (CF) diagnosed following newborn screening. 184 children (aged 3–6 years) with CF underwent lung function testing on 422 occasions using the FOT to assess respiratory resistance and reactance at the time of their annual bronchoalveolar lavage collection and chest computed tomography scan. We examined associations between FOT outcomes and the presence and progression of respiratory inflammation, infection and structural lung disease. Children with CF who had pronounced respiratory disease, including free neutrophil elastase activity, infection with pro-inflammatory pathogens and structural lung abnormalities had similar FOT outcomes to those children without detectable lung disease. In addition, the progression of lung disease over 1 year was not associated with worsening FOT outcomes. We conclude that the forced oscillation technique is relatively insensitive to detect underlying lung disease in preschool children with CF. However, FOT may still be of value in improving our understanding of the physiological changes associated with early CF lung disease

Structural determinants of long-term functional outcomes in young children with cystic fibrosis

BACKGROUND: Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients. METHODS: Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5-6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean±sd age 9.3±2.1 years). RESULTS: Children with a total CT score above the median at age 5-6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV1) (adjusted hazard ratio 2.67 (1.06-6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26 - -0.07) p<0.001 and -0.09 (-0.14 - -0.04) p<0.001, respectively). DISCUSSION: Chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success

Intra-breath measures of respiratory mechanics in healthy African infants detect risk of respiratory illness in early life

Lower respiratory tract illness (LRTI) is a leading cause of mortality and morbidity in children. Sensitive and noninvasive infant lung function techniques are needed to measure risk for and impact of LRTI on lung health. The objective of this study was to investigate whether lung function derived from the intra-breath forced oscillation technique (FOT) was able to identify healthy infants at risk of LRTI in the first year of life. Lung function was measured with the novel intra-breath FOT, in 6-week-old infants in a South African birth cohort (Drakenstein Child Health Study). LRTI during the first year was confirmed by study staff. The association between baseline lung function and LRTI was assessed with logistic regression and odds ratios determined using optimal cut-off values. Of the 627 healthy infants with successful lung function testing, 161 (24%) had 238 LRTI episodes subsequently during the first year. Volume dependence of respiratory resistance (ΔR) and reactance (ΔX) was associated with LRTI. The predictive value was stronger if LRTI was recurrent (n=50 (31%): OR 2.5, ΔX), required hospitalisation (n=38 (16%): OR 5.4, ΔR) or was associated with wheeze (n=87 (37%): OR 3.9, ΔX). Intra-breath FOT can identify healthy infants at risk of developing LRTI, wheezing or severe illness in the first year of life