NCT Molecular Diagnostics Program

The NCT Precision Oncology Program (NCT POP) provides a comprehensive platform for individualized cancer medicine. To streamline molecular diagnostics, we have created the Heidelberg Center for Personalized Oncology (DKFZ-HIPO), a dedicated genomics and bioinformatics platform for clinical translation.

Molecular Diagnostics
 

DKFZ-HIPO combines molecular diagnostics and systems biology with innovative therapeutics development and interdisciplinary patient care to define molecularly stratified patient cohorts and hypothesis-driven treatments within the clinical implementation workflow of NCT POP.

The program, which is based on the ICGC experience, has so far sequenced >800 samples. The national Heidelberg-led INFORM study, which enrolls all children and adolescents with relapsed or refractory cancers in Germany for comprehensive molecular profiling, is the first nationally comprehensive initiative to translate personalized treatment into clinical practice. In adult oncology, a pilot protocol (NCT IMPACT) for adult cancer patients with a particularly challenging disease course and surprise responders has enrolled more than 60 patients and identified actionable genetic lesions in a substantial proportion of cases, such as BRAF inhibition in refractory hairy-cell leukemia (Dietrich N Engl J Med 2012). In 2014, NCT exome and transcriptome sequencing via NCT MASTER will focus on all adult patients with systemic cancers who are younger than 50 and undergo biopsy or resection of their tumors at NCT/HUMS. The NCT Neuro MASTER MATCH trial uses obligatory genome-wide methylation analyses and a glioma gene panel to treat newly diagnosed glioma as a paradigm for other entities. A center-wide roll-out of NCT MASTER for patients of all ages is scheduled to begin in 2015, with the aim of providing all relevant information on the molecular status of every tumor as a stratification tool for each individual NCT patient at every major treatment decision milestone.

Building on these achievements, NCT POP leverages existing expertise beyond cancer genomics to work towards comprehensive, multidimensional characterization of all cancer patients seen at NCT/HUMS. Important examples include systematic epigenetic profiling, detailed quantitative immunomics, and characterization of the tumor-initiating cell compartment in various cancers. Additional layers of characterization focus on determining the functional properties of specific cancer genotypes – using both genetic and pharmacologic perturbations – and systematic proteomic studies of primary human cancer specimen.

Molecular Diagnostics

Recent Discoveries

(1) FGFR1 and NTRK2 alterations in pilocytic astrocytoma (Jones Nat Genet 2013), (2) androgen-driven somatic alteration early-onset prostate cancer (Weischenfeldt Cancer Cell 2013), (3) ID3 mutations in Burkitt lymphoma (Richter Nat Genet 2012), (4) driver mutations in histone H3.3 and chromatin remodeling genes in pediatric glioblastoma (Schwartzentruber Nature 2012), (5) genome sequencing of pediatric medulloblastoma (Jones Nature 2012; Rausch Cell 2012¸ Korshunov J Clin Oncol 2010), (6) Wiskott-Aldrich Syndrome gene therapy (Boztug N Engl J Med 2010), (7) genomic instability after EVI1 activation (Stein Nat Med 2010), and (8) zinc-finger nuclease specificity (Gabriel Nature Biotech 2011).