Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5–52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

Association between solar insolation and a history of suicide attempts in bipolar I disorder

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p <0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.Peer reviewe

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p &lt; 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed

Changes in Colorectal Carcinoma Genomes under Anti-EGFR Therapy Identified by Whole-Genome Plasma DNA Sequencing

<div><p>Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i>, and <i>EGFR</i>. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of <i>KRAS</i> in four patients (40%), which occurred either as novel focal amplifications (<i>n</i> = 3) or as high level polysomy of 12p (<i>n</i> = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as <i>MET</i> (<i>n</i> = 2) and <i>ERBB2</i> (<i>n</i> = 1). Overrepresentation of the <i>EGFR</i> gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i>, and <i>EGFR</i> did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.</p></div

Co-occurrence of amplifications of the <i>KRAS</i> and <i>MET</i> genes observed after 7 months of treatment with panitumumab in patient #4.

<p>(a) Copy number profiles of the primary tumor (PT4) and the plasma DNA (P4_1) obtained 15 months later. The focal amplifications of the <i>MET</i> and <i>KRAS</i> genes on chromosomes 7 and 12, respectively, are annotated in the plasma sample. (b) The units in the time line correspond to months. Above the time line the period of panitumumab therapy and the CEA (ng/ml) and CA 19-9 (U/ml) (in blue and red, respectively) levels are illustrated.</p

Cases with copy number changes in <i>EGFR</i>, <i>MET</i>, and <i>ERBB2</i>.

<p>(a) Copy number profiles of the primary tumor (PT5) and a plasma sample (P5_1) of patient #5, the time interval between both samples is almost 3 years. Both samples show a focal amplification of the <i>MET</i> gene and, furthermore regions on 7p and 17q, harboring the <i>EGFR</i> and the <i>ERBB2</i> genes, respectively, are gained. The focal amplification on chromosome 12q13.13-12q13.3 does not include the <i>KRAS</i> gene (for further details see text). (b) Plasma-Seq for patient #6 prior to anti-EGFR therapy with cetuximab (P6_1) showed several copy number changes, including gains of 7p (<i>EGFR</i>) and 17q (<i>ERBB2</i>). The time line indicates the low CEA and CA 19-9 levels during treatment with cetuximab. (FOLFOX: FOL-Folinic acid (leucovorin) + F-Fluorouracil (5-FU) + OX-Oxaliplatin (Eloxatin); FOLFIRI: FOL-Folinic acid (leucovorin) + F-Fluorouracil (5-FU) + IRI-irinotecan).</p

Patients' clinical characteristics.

1<p>Sample names starting with “PT” indicate those derived from primary tumors, with “M” from a metastatic lesion, “LM” from a liver metastasis, and “P” indicates the plasma samples.</p

High-level focal amplification of <i>ERBB2</i> in patient #7 treated with cetuximab.

<p>(a) Copy number profile of the plasma sample (P7_1) and the locations of the <i>EGFR</i>, <i>MET</i>, <i>KRAS</i>, and <i>ERBB2</i> genes. (b) The time line illustrates the duration of cetuximab treatment and the date (red bar) of our blood collection. Below the time line are the ERBB2 immunohistochemistry and silver in situ hybridization (SISH) images of the biopsy material from the primary tumor (month 0) showing an immunoreactive score 3+ and high amplification, respectively. Her2/neu signals are black in the SISH technique. Furthermore, a plot of chromosome 17 from P7_1 obtained at month 14 is illustrated (note that the scale of the Y-axis reaches till 5 to illustrate the high-level gain; color designation as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004271#pgen-1004271-g001" target="_blank">Figure 1</a>).</p

Appearance of <i>KRAS</i> amplification after 6 months of panitumumab therapy in patient #2.

<p>(a) Copy number analyses of the primary tumor (PT2) and three plasma analyses (P2_1, month 27; P2_2, month 29; and P2_3, month 33). The locations of the <i>EGFR</i>, <i>ERBB2</i> and <i>KRAS</i> genes are indicted in PT2 and P2_3, respectively. The dates of plasma sampling are shown in (b). (b) The timeline indicates the dates of our blood collections (red bars), the duration of the panitumumab therapy, and the respective CEA (ng/ml) and CA 19-9 (U/ml) (in blue and red, respectively) values.</p