Summary
Background
An epidemic of basal cell carcinoma (BCC) has led to a significant healthcare burden in white populations.
Objectives
To provide an update on incidence rates and tumour burden in ...an unselected, geographically isolated population that is exposed to a low level of ultraviolet radiation.
Methods
This was a whole‐population study using a cancer registry containing records of all cases of BCC in 1981–2017. We assessed BCC incidence according to age, residence and multiplicity and assessed trends using join‐point analysis. Age‐standardized and age‐specific incidence rates were calculated along with cumulative and lifetime risks.
Results
During the study period, the age‐standardized incidence rates increased from 25·7 to 59·9 for men, and from 22·2 to 83·1 for women (per 100 000). Compared with the single‐tumour burden, the total tumour burden in the population was 1·72 times higher when accounting for multiplicity. At the beginning of the study period, the world‐standardized rates in men and women were similar, but by the end of the study period the rates were 39% higher in women (83·1 per 100 000, 95% confidence interval 77·9–88·3) than in men (59·9 per 100 000, 95% confidence interval 55·6–64·2). This increase was most prominent in women on sites that are normally not exposed to ultraviolet radiation in Iceland: the trunk and legs.
Conclusions
This is the only reported population in which the incidence of BCC is significantly higher in women than in men. The period of notable increase in BCC lesions correlates with the period of an increase in tanning beds and travel popularity. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought.
What is already known about this topic?
Basal cell carcinoma (BCC) is becoming an increasing healthcare burden worldwide, especially in white populations.
Recent population studies have reported a rapid increase in incidence among younger individuals, especially women.
What does this study add?
Iceland is the only reported population in which the incidence of BCC is significantly higher in women than in men, and there does not seem to be a clear relationship between latitude and BCC incidence in Europe.
Men might be comparatively protected in the northern low‐ultraviolet environment, with tanning beds and travel abroad likely playing important roles in the observed incidence increase, especially in women.
The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought.
Linked Comment: Pandeya. Br J Dermatol 2020; 183:799–800.
What is already known about this topic?
Basal cell carcinoma (BCC) is becoming an increasing healthcare burden worldwide, especially in white populations.
Recent population studies have reported a rapid increase in incidence among younger individuals, especially women.
What does this study add?
Iceland is the only reported population in which the incidence of BCC is significantly higher in women than in men, and there does not seem to be a clear relationship between latitude and BCC incidence in Europe.
Men might be comparatively protected in the northern low‐ultraviolet environment, with tanning beds and travel abroad likely playing important roles in the observed incidence increase, especially in women.
The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought.
Linked Comment: Pandeya. Br J Dermatol 2020; 183:799–800.
Plain language summary available online
Level set techniques are numerical techniques for tracking the evolution of interfaces. They rely on two central embeddings; first, the embedding of the interface as the zero level set of a higher ...dimensional function, and second, the embedding (or extension) of the interface's velocity to this higher dimensional level set function. This paper applies Sethian's Fast Marching Method, which is a very fast technique for solving the eikonal and related equations, to the problem of building fast and appropriate extension velocities for the neighboring level sets. Our choice and construction of extension velocities serves several purposes. First, it provides a way of building velocities for neighboring level sets in the cases where the velocity is defined only on the front itself. Second, it provides a subgrid resolution not present in the standard level set approach. Third, it provides a way to update an interface according to a given velocity field prescribed on the front in such a way that the signed distance function is maintained, and the front is never re-initialized; this is valuable in many complex simulations. In this paper, we describe the details of such implementations, together with speed and convergence tests and applications to problems in visibility relevant to semi-conductor manufacturing and thin film physics.
Little is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 ...mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure.
We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR).
Pre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy.
Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.
•We analyzed mechanisms of resistance to PARP inhibitor/platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer.•Genomic reversion to functional BRCA1/2 protein was identified in one-half of patients.•Up-regulation of DNA end resection was identified as a resistance mechanism in two additional patients.•RAD51 foci assessed by immunohistochemistry correlated with clinical response to PARP inhibitor/platinum.•RAD51 focus staining warrants further exploration as a biomarker for clinical use.
We develop theory and numerical algorithms to apply level set methods to problems involving the transport and diffusion of material quantities in a level set framework. Level set methods are ...computational techniques for tracking moving interfaces; they work by embedding the propagating interface as the zero level set of a higher dimensional function, and then approximate the solution of the resulting initial value partial differential equation using upwind finite difference schemes. The traditional level set method works in the trace space of the evolving interface, and hence disregards any parameterization in the interface description. Consequently, material quantities on the interface which themselves are transported under the interface motion are not easily handled in this framework. We develop model equations and algorithmic techniques to extend the level set method to include these problems. We demonstrate the accuracy of our approach through a series of test examples and convergence studies.
Fire is a powerful ecological and evolutionary force that regulates organismal traits, population sizes, species interactions, community composition, carbon and nutrient cycling and ecosystem ...function. It also presents a rapidly growing societal challenge, due to both increasingly destructive wildfires and fire exclusion in fire‐dependent ecosystems. As an ecological process, fire integrates complex feedbacks among biological, social and geophysical processes, requiring coordination across several fields and scales of study.
Here, we describe the diversity of ways in which fire operates as a fundamental ecological and evolutionary process on Earth. We explore research priorities in six categories of fire ecology: (a) characteristics of fire regimes, (b) changing fire regimes, (c) fire effects on above‐ground ecology, (d) fire effects on below‐ground ecology, (e) fire behaviour and (f) fire ecology modelling.
We identify three emergent themes: the need to study fire across temporal scales, to assess the mechanisms underlying a variety of ecological feedbacks involving fire and to improve representation of fire in a range of modelling contexts.
Synthesis: As fire regimes and our relationships with fire continue to change, prioritizing these research areas will facilitate understanding of the ecological causes and consequences of future fires and rethinking fire management alternatives.
We describe the diversity of ways in which fire operates as a fundamental ecological and evolutionary process on Earth. We explore research priorities in six categories of fire ecology. We identify three needs: to study fire across temporal scales, to assess the mechanisms underlying a variety of ecological feedbacks involving fire and to improve representation of fire in modeling contexts.
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular ...heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed ...linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%–87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.
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•Linked-read genome sequencing of mCRPC resolves haplotypes and rearrangements•CDK12 inactivation is associated with a global tandem duplication phenotype•A majority of cases have duplications of an enhancer of the androgen receptor•Progression on androgen pathway inhibitors is associated with gains in AR and AR enhancer
Linked-read genome sequencing data from patients highlight that amplification of an enhancer upstream of the androgen receptor locus is a key feature of metastatic castration-resistant prostate cancer.
Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding ...the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to ...these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.
Glioblastomas (GBM) with EGFR amplification represent approximately 50% of newly diagnosed cases, and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same ...tumor, which has implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here, we applied a population-based single-cell whole-genome sequencing methodology to characterize genomic heterogeneity in EGFR-amplified glioblastomas. Our analysis effectively identified clonal events, including a novel translocation of a super enhancer to the TERT promoter, as well as subclonal LOH and multiple EGFR mutational variants within tumors. Correlating the EGFR mutations onto the cellular hierarchy revealed that EGFR truncation variants (EGFRvII and EGFR carboxyl-terminal deletions) identified in the bulk tumor segregate into nonoverlapping subclonal populations. In vitro and in vivo functional studies show that EGFRvII is oncogenic and sensitive to EGFR inhibitors currently in clinical trials. Thus, the association between diverse activating mutations in EGFR and other subclonal mutations within a single tumor supports an intrinsic mechanism for proliferative and clonal diversification with broad implications in resistance to treatment.
We developed a novel single-cell sequencing methodology capable of identifying unique, nonoverlapping subclonal alterations from archived frozen clinical specimens. Using GBM as an example, we validated our method to successfully define tumor cell subpopulations containing distinct genetic and treatment resistance profiles and potentially mutually cooperative combinations of alterations in EGFR and other genes.
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