Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Gratings for synchrotron and FEL beamlines: a project for the manufacture of ultra-precise gratings at Helmholtz Zentrum Berlin.

Blazed gratings are of dedicated interest for the monochromatization of synchrotron radiation when a high photon flux is required, such as, for example, in resonant inelastic X-ray scattering experiments or when the use of laminar gratings is excluded due to too high flux densities and expected damage, for example at free-electron laser beamlines. Their availability became a bottleneck since the decommissioning of the grating manufacture facility at Carl Zeiss in Oberkochen. To resolve this situation a new technological laboratory was established at the Helmholtz Zentrum Berlin, including instrumentation from Carl Zeiss. Besides the upgraded ZEISS equipment, an advanced grating production line has been developed, including a new ultra-precise ruling machine, ion etching technology as well as laser interference lithography. While the old ZEISS ruling machine GTM-6 allows ruling for a grating length up to 170 mm, the new GTM-24 will have the capacity for 600 mm (24 inch) gratings with groove densities between 50 lines mm-1 and 1200 lines mm-1. A new ion etching machine with a scanning radiofrequency excited ion beam (HF) source allows gratings to be etched into substrates of up to 500 mm length. For a final at-wavelength characterization, a new reflectometer at a new Optics beamline at the BESSY-II storage ring is under operation. This paper reports on the status of the grating fabrication, the measured quality of fabricated items by ex situ and in situ metrology, and future development goals.

Highly efficient blazed grating with multilayer coating for tender X-ray energies.

For photon energies of 1 - 5 keV, blazed gratings with multilayer coating are ideally suited for the suppression of stray and higher orders light in grating monochromators. We developed and characterized a blazed 2000 lines/mm grating coated with a 20 period Cr/C- multilayer. The multilayer d-spacing of 7.3 nm has been adapted to the line distance of 500 nm and the blaze angle of 0.84° in order to provide highest efficiency in the photon energy range between 1.5 keV and 3 keV. Efficiency of the multilayer grating as well as the reflectance of a witness multilayer which were coated simultaneously have been measured. An efficiency of 35% was measured at 2 keV while a maximum efficiency of 55% was achieved at 4 keV. In addition, a strong suppression of higher orders was observed which makes blazed multilayer gratings a favorable dispersing element also for the low X-ray energy range.