Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

State of nature

For the first time ever, the UK’s wildlife organisations have joined forces to undertake a health check of nature in the UK and its Overseas Territories. 60% of the 3,148 UK species we assessed have declined over the last 50 years and 31% have declined strongly. Half of the species assessed have shown strong changes in their numbers or range, indicating that recent environmental changes are having a dramatic impact on nature in the UK. Species with specific habitat requirements seem to be faring worse than generalist species. A new Watchlist Indicator, developed to measure how conservation priority species are faring, shows that their overall numbers have declined by 77% in the last 40 years, with little sign of recovery. Of more than 6,000 species that have been assessed using modern Red List criteria, more than one in 10 are thought to be under threat of extinction in the UK. Our assessment looks back over 50 years at most, yet there were large declines in the UK’s wildlife prior to this, linked to habitat loss. The UK’s Overseas Territories hold a wealth of wildlife of huge international importance and over 90 of these species are at high risk of global extinction. There is a lack of knowledge on the trends of most of the UK’s species. As a result, we can report quantitative trends for only 5% of the 59,000 or so terrestrial and freshwater species in the UK, and for very few of the 8,500 marine species. Much needs to be done to improve our knowledge. What we do know about the state of the UK’s nature is often based upon the efforts of thousands of dedicated volunteer enthusiasts who contribute their time and expertise to monitoring schemes and species recording. The threats to the UK’s wildlife are many and varied, the most severe acting either to destroy valuable habitat or degrade the quality and value of what remains. Climate change is having an increasing impact on nature in the UK. Rising average temperatures are known to be driving range expansion in some species, but evidence for harmful impacts is also mounting. The full report is online: www.rspb.org.uk/stateofnature We should act to save nature both for its intrinsic value and for the benefits it brings to us that are essential to our wellbeing and prosperity. Targeted conservation has produced inspiring success stories and, with sufficient determination, resources and public support, we can turn the fortunes of our wildlife around. The State of Nature report serves to illustrate that with shared resolve and commitment we can save nature

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease