Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and ...BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.
Highlights • It is unclear whether the different reproductive behaviors predispose or protect against certain subtype of breast cancer over the other. • This meta-analysis evaluated the association ...between parity, age at first birth, breastfeeding and the risk of developing breast cancer according to tumor subtype (i.e. luminal, HER2-positive and triple-negative). • Parity was significantly associated with a 25% reduced risk of developing luminal subtype. • Advanced age at first birth was significantly associated with a 15% increased risk of developing luminal subtype. • Ever breastfeeding was significantly associated with a 23% and 21% reduced risk of developing both luminal and triple-negative subtypes, respectively.
gene clusters encode transcription factors that drive regional specialization during animal development: for example the Hox factor Ubx is expressed in the insect metathoracic (T3) wing appendages ...and differentiates them from T2 mesothoracic identities.
transcriptional regulation requires silencing activities that prevent spurious activation and regulatory crosstalks in the wrong tissues, but this has seldom been studied in insects other than
, which shows a derived
dislocation into two genomic clusters that disjoined
(
) and
(
). Here, we investigated how
is restricted to the hindwing in butterflies, amidst a contiguous
cluster. By analysing Hi-C and ATAC-seq data in the butterfly
, we show that a Topologically Associated Domain (TAD) maintains a hindwing-enriched profile of chromatin opening around
. This TAD is bordered by a Boundary Element (BE) that separates it from a region of joined wing activity around the
locus. CRISPR mutational perturbation of this BE releases ectopic
expression in forewings, inducing homeotic clones with hindwing identities. Further mutational interrogation of two non-coding RNA encoding regions and one putative
regulatory module within the
TAD cause rare homeotic transformations in both directions, indicating the presence of both activating and repressing chromatin features. We also describe a series of spontaneous forewing homeotic phenotypes obtained in
butterflies, and discuss their possible mutational basis. By leveraging the extensive wing specialization found in butterflies, our initial exploration of
regulation demonstrates the existence of silencing and insulating sequences that prevent its spurious expression in forewings.
To what extent can we predict how evolution occurs? Do genetic architectures and developmental processes canalize the evolution of similar outcomes in a predictable manner? Or do historical ...contingencies impose alternative pathways to answer the same challenge? Examples of Müllerian mimicry between distantly related butterfly species provide natural replicates of evolution, allowing us to test whether identical wing patterns followed parallel or novel trajectories. Here, we explore the role that the signaling ligand WntA plays in generating mimetic wing patterns in Heliconius butterflies, a group with extraordinary mimicry-related wing pattern diversity. The radiation is relatively young, and numerous cases of wing pattern mimicry have evolved within the last 2.5–4.5 Ma. WntA is an important target of natural selection and is one of four major effect loci that underlie much of the pattern variation in the group. We used CRISPR/Cas9 targeted mutagenesis to generate WntA-deficient wings in 12 species and a further 10 intraspecific variants, including three co-mimetic pairs. In all tested butterflies, WntA knockouts affect pattern broadly and cause a shift among every possible scale cell type. Interestingly, the co-mimics lacking WntA were very different, suggesting that the gene networks that pattern a wing have diverged considerably among different lineages. Thus, although natural selection channeled phenotypic convergence, divergent developmental contexts between the two major Heliconius lineages opened different developmental routes to evolve resemblance. Consequently, even under very deterministic evolutionary scenarios, our results underscore a surprising unpredictability in the developmental paths underlying convergence in a recent radiation.
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•Mimicry in Heliconius is achieved through divergent developmental networks•WntA is a major patterning gene that is used differently in co-mimics•Regulation of WntA expression and its interaction with other genes shape diversity•WntA modulates wing-scale cell identity
Concha et al. use CRISPR/Cas9 genome editing to knock out a major wing patterning gene, WntA, in mimetic species of Heliconius butterflies and report that WntA is used in divergent gene regulatory networks in co-mimics and that resemblance is achieved through differential expression of WntA and its interaction with the specific genetic background.
Butterfly wing patterns have emerged as exceptional model systems with which to link the developmental and genetic processes that generate morphological variation with the ecological and evolutionary ...processes that shape this variation in natural populations. Among butterflies, research on species within the genus Heliconius has provided remarkable opportunities to explore how phenotypic diversity is generated within the context of an extraordinary adaptive radiation. Wing pattern diversity among the 48 species and hundreds of intraspecific variants arose within the last 12–14 million years and includes striking pattern convergence between distantly related species, as well as marked pattern divergence between closely related populations and species. Here, we synthesize recent research aimed at gaining a mechanistic understanding of how this variation is generated. This research integrates decades of controlled crossing experiments, and the discovery of major wing patterning genes (optix, aristaless1, WntA and cortex) with recent functional genetic manipulation using CRISPR/Cas9 targeted mutagenesis. The emerging data provides a rich framework with which to explore the repeatability of evolution, particularly within the context of how natural selection acts on divergent gene regulatory networks to generate both highly convergent, as well as highly divergent phenotypes. Overall, the functional data show that the gene regulatory networks underlying pattern variation diverge rapidly in Heliconius; yet these networks retain enough flexibility so that natural selection can drive the evolution of nearly identical patterns from different developmental genetic starting points. Moreover, for the first time this research is starting to illuminate the links between the genetic changes modulating pattern variation and how they influence the larger gene networks that are ultimately responsible for patterning a butterfly wing. There are still large gaps in our understanding, but current research priorities are well laid out and experimental methodologies are in place to address them. The challenge is to synthesize diverse research strategies into a cohesive picture of morphological evolution.
In
butterflies, wing colour pattern diversity and scale types are controlled by a few genes of large effect that regulate colour pattern switches between morphs and species across a large mimetic ...radiation. One of these genes,
, has been repeatedly associated with colour pattern evolution in butterflies. Here we carried out CRISPR knockouts in multiple
species and show that
is a major determinant of scale cell identity. Chromatin accessibility profiling and introgression scans identified
-regulatory regions associated with discrete phenotypic switches. CRISPR perturbation of these regions in black hindwing genotypes recreated a yellow bar, revealing their spatially limited activity. In the
lineage, the candidate CRE from yellow-barred phenotype morphs is interrupted by a transposable element, suggesting that
-regulatory structural variation underlies these mimetic adaptations. Our work shows that
functionally controls scale colour fate and that its
-regulatory regions control a phenotypic switch in a modular and pattern-specific fashion.
A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can ...spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria. We conclude that vertically transmitted rhabdoviruses may be widespread in a broad range of insect taxa, and that these viruses can have dynamic interactions with their hosts.
•We reported the results of a retrospective study performed on elderly breast cancer patients enrolled in 3 onco-geriatric trials coordinated by the medical oncology division of the Hospital of ...Prato. This analysis suggests that a metabolomic signature, identified employing NMR spectral profiling, is able to predict the risk of disease recurrence in elderly patients with early breast cancer, independently from classical clinicopathological features. The metabolomic signature is a prognostic marker that takes into account not only the tumor but also the host. This is particularly relevant in the elderly, due to the heterogeneity of this population, and particularly in older patients with early breast cancer in whom other causes of death can compete with breast cancer in determining patients’ outcome.
We previously showed that metabolomics predicts relapse in early breast cancer (eBC) patients, unselected by age. This study aims to identify a “metabolic signature” that differentiates eBC from advanced breast cancer (aBC) patients, and to investigate its potential prognostic role in an elderly population.
Serum samples from elderly breast cancer (BC) patients enrolled in 3 onco-geriatric trials, were retrospectively analyzed via proton nuclear magnetic resonance (1H NMR) spectroscopy. Three nuclear magnetic resonance (NMR) spectra were acquired for each serum sample: NOESY1D, CPMG, Diffusion-edited. Random Forest (RF) models to predict BC relapse were built on NMR spectra, and resulting RF risk scores were evaluated by Kaplan–Meier curves.
Serum samples from 140 eBC patients and 27 aBC were retrieved. In the eBC cohort, median age was 76 years; 77% of patients had luminal, 10% HER2-positive and 13% triple negative (TN) BC. Forty-two percent of patients had tumors >2 cm, 43% had positive axillary nodes. Using NOESY1D spectra, the RF classifier discriminated free-from-recurrence eBC from aBC with sensitivity, specificity and accuracy of 81%, 67% and 70% respectively. We tested the NOESY1D spectra of each eBC patient on the RF models already calculated. We found that patients classified as "high risk" had higher risk of disease recurrence (hazard ratio (HR) 3.42, 95% confidence interval (CI) 1.58–7.37) than patients at low-risk.
This analysis suggests that a “metabolic signature”, identified employing NMR fingerprinting, is able to predict the risk of disease recurrence in elderly patients with eBC independently from standard clinicopathological features.
As the genetic basis of natural and domesticated variation has been described in recent years, a number of hotspot genes have been repeatedly identified as the targets of selection, Heliconius ...butterflies display a spectacular diversity of pattern variants in the wild and the genetic basis of these patterns has been well-described. Here, we sought to identify the mechanism behind an unusual pattern variant that is instead found in captivity, the ivory mutant, in which all scales on both the wings and body become white or yellow. Using a combination of autozygosity mapping and coverage analysis from 37 captive individuals, we identify a 78-kb deletion at the cortex wing patterning locus, a gene which has been associated with wing pattern evolution in H. melpomene and 10 divergent lepidopteran species. This deletion is undetected among 458 wild Heliconius genomes samples, and its dosage explains both homozygous and heterozygous ivory phenotypes found in captivity. The deletion spans a large 5' region of the cortex gene that includes a facultative 5'UTR exon detected in larval wing disk transcriptomes. CRISPR mutagenesis of this exon replicates the wing phenotypes from coding knock-outs of cortex, consistent with a functional role of ivory-deleted elements in establishing scale color fate. Population demographics reveal that the stock giving rise to the ivory mutant has a mixed origin from across the wild range of H. melpomene, and supports a scenario where the ivory mutation occurred after the introduction of cortex haplotypes from Ecuador. Homozygotes for the ivory deletion are inviable while heterozygotes are the targets of artificial selection, joining 40 other examples of allelic variants that provide heterozygous advantage in animal populations under artificial selection by fanciers and breeders. Finally, our results highlight the promise of autozygosity and association mapping for identifying the genetic basis of aberrant mutations in captive insect populations.
Germline pathogenic variants (PVs) in the
or
genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The ...aim of this study was to compare the
PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019
PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo
PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo
PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.
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