Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected ...by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness") by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.
Expression of
HOX transcript antisense intergenic
RNA (
HOTAIR
)—a long non-coding RNA—has been examined in a variety of human cancers, and overexpression of
HOTAIR
is correlated with poor survival ...among breast, colon, and liver cancer patients. In this retrospective study, we examine
HOTAIR
expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that
HOTAIR
expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high
HOTAIR
expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (
P
= 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (
P
= 0.0086, HR 1.985). In ER-negative tumor samples, we are not able to detect a prognostic value of
HOTAIR
expression, probably due to the limited sample size. These results are successfully validated in an independent dataset with similar associations (
P
= 0.018, HR 1.825). In conclusion, our findings suggest that
HOTAIR
expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
•Bipolar disorder (BD) is characterized by aberrant neurophysiological responses in the gamma range.•Systematic review and meta-analysis shows reduced 40 Hz auditory steady-state responses (ASSR) in ...BD.•40-Hz ASSR deficits may represent a transdiagnostic biomarker of neuronal circuit dysfunction.
Bipolar disorder is characterized by aberrant neurophysiological responses as measured with electroencephalography (EEG) and magnetoencephalography (MEG), including the 40-Hz auditory steady-state response (ASSR). 40-Hz ASSR deficits are also found in patients with schizophrenia and may represent a transdiagnostic biomarker of neuronal circuit dysfunction. In this systematic review and meta-analysis, we summarize and evaluate the evidence for 40-Hz ASSR deficits in patients with bipolar disorder.
We identified studies from PubMed, EMBASE, and SCOPUS. We assessed the risk of bias, calculated Hedges’ g meta-level effect sizes, and investigated small-study effects using funnel plots and Egger regression.
Seven studies, comprising 396 patients with bipolar disorder and 404 healthy controls, were included in the meta-analysis. Studies displayed methodological heterogeneity and an overall high risk of bias. Patients with bipolar disorder showed consistent reductions in 40-Hz ASSR evoked power (Hedges’ g = −0.49; 95% confidence intervals −0.67, −0.31) and inter-trial phase coherence (ITPC) (Hedges’ g = −0.43; 95 %CI −0.58, −0.29) compared with healthy controls.
Our meta-analysis provides evidence that 40-Hz ASSRs are reduced in patients with bipolar disorder compared with healthy controls.
Future large-scale studies are warranted to link 40-Hz ASSR deficits to clinical features and developmental trajectories.
Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of ...BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown.
We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers.
We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent.
A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.
Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
We identified two families ...with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.
Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.
This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
Key points
What's already known about this topic?
Non‐invasive prenatal testing (NIPT) is a sensitive and risk‐free prenatal screening test for common aneuploidies.
Until now, NIPT has required ...access to expensive next generation sequencing (NGS) sequencers, making it only accessible to large laboratories.
What does this study add?
This proof‐of‐concept study demonstrates that Oxford Nanopore platform, originally developed for long‐reads, can be used to sequence and analyze short cell‐free DNA (cfDNA) fragments with high efficiency and accuracy.
We developed nanoNIPT for non‐invasive detection of fetal aneuploidies and sex chromosome aberrations, which enables NIPT testing without large upfront investments making it accessible in all the clinical labs around the world.
Only few studies have investigated the genomewide transcriptome of normative cognitive aging. We therefore aimed at investigating blood gene expression patterns associated with cognitive aging using ...a population-based sample of 235 middle-aged monozygotic twin pairs with longitudinal data on cognitive function. This unique setup enabled examination of gene expression differences associated with individual and intrapair differences in cognitive level and change while controlling for underlying genetic variation and shared early environment. Overall, increased expression of several gene sets was found to strongly correlate with a lower cognitive level and cognitive decline. The most significantly correlated gene sets were related to protein metabolism, translation, RNA metabolism, infectious disease, and the immune system, which are all processes previously linked to transcription signatures of pathological and normal brain aging, and aging in blood. The results of our study thus suggest that gene expression patterns of cognitive level and decline in our sample mirror those seen in cognitively impaired individuals, which could point toward a more generic response to cognitive aging and aging in general.
•Several gene sets significantly correlate with cognitive function and change.•They are protein and RNA metabolism; translation; infectious disease; immune system.•These processes have previously been linked to brain aging and aging in blood.•This points to a generic transcriptional response to cognitive and general aging.
U–Pb geochronology of shocked monazite can be used to date hypervelocity impact events. Impact-induced recrystallisation and formation of mechanical twins in monazite have been shown to result in ...radiogenic Pb loss and thus constrain impact ages. However, little is known about the effect of porosity on the U–Pb system in shocked monazite. Here we investigate monazite in two impact melt rocks from the Hiawatha impact structure, Greenland by means of nano- and micrometre-scale techniques. Microstructural characterisation by scanning electron and transmission electron microscopy imaging and electron backscatter diffraction reveals shock recrystallisation, microtwins and the development of widespread micrometre- to nanometre-scale porosity. For the first time in shocked monazite, nanophases identified as cubic Pb, Pb
3
O
4
, and cerussite (PbCO
3
) were observed. We also find evidence for interaction with impact melt and fluids, with the formation of micrometre-scale melt-bearing channels, and the precipitation of the Pb-rich nanophases by dissolution–precipitation reactions involving pre-existing Pb-rich high-density clusters. To shed light on the response of monazite to shock metamorphism, high-spatial-resolution U–Pb dating by secondary ion mass spectrometry was completed. Recrystallised grains show the most advanced Pb loss, and together with porous grains yield concordia intercept ages within uncertainty of the previously established zircon U–Pb impact age attributed to the Hiawatha impact structure. Although porous grains alone yielded a less precise age, they are demonstrably useful in constraining impact ages. Observed relatively old apparent ages can be explained by significant retention of radiogenic lead in the form of widespread Pb nanophases. Lastly, we demonstrate that porous monazite is a valuable microtexture to search for when attempting to date poorly constrained impact structures, especially when shocked zircon or recrystallised monazite grains are not present.
Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses. Mutations in SHANK genes are associated with autism and intellectual disability. The effects of missense ...mutations on Shank3 function, and therefore the pathomechanisms are unclear. Several missense mutations in SHANK3 affect the N-terminal region, consisting of the Shank/ProSAP N-terminal (SPN) domain and a set of Ankyrin (Ank) repeats. Here we identify a novel SHANK3 missense mutation (p.L270M) in the Ankyrin repeats in patients with an ADHD-like phenotype. We functionally analysed this and a series of other mutations, using biochemical and biophysical techniques. We observe two major effects: (1) a loss of binding to δ-catenin (e.g. in the p.L270M variant), and (2) interference with the intramolecular interaction between N-terminal SPN domain and the Ank repeats. This also interferes with binding to the α-subunit of the calcium-/calmodulin dependent kinase II (αCaMKII), and appears to be associated with a more severe neurodevelopmental pathology.
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