Coding and non-coding genomic drivers
Genomic drivers of rare cancer entities
Cancer is commonly regarded as 'a disease of the genes'. Alterations in abundance (copy number variation – CNV) or sequence (single nucleotide variation – SNV, insertions, deletions) and larger genomic rearrangements indeed affect individual or many genes thus contributing to disease onset and progression.
Enhancer hijacking is the main driver mechanism in acinic cell carcinoma of the salivary glands (AciCC). Haller et al. 2019 Nat Commun, 10(1):368
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With Florian Haller and Arndt Hartmann (University Clinics Erlangen) we have unveiled and experimentally verified molecular driver alterations in rare tumor entities. Enhancer hijacking activates gene expression of transcription factor NR4A3 as a driver mechanism in acinic cell carcinoma of the salivary gland (Haller et al. 2019 Nat Commun, 10(1):368; Haller et al. 2019 Am J Surg Pathol, 43(9):1264-72; Haller et al. 2020 Am J Surg Pathol, 44(9):1290-92).
Figure 1: Mapping of t(4;9)(q13;q31) chromosomal breakpoints of six AciCCs as determined by WGS spanning the SCPP gene cluster (Chr4), and clustering of breakpoints upstream of the NR4A3 gene locus (Chr 9q31). Circos plots of translocations in two AciCC cases, with recurrent rearrangements t(4;9)(q13;q31) highlighted in red. mRNA expression (log2 FPKM values) of NR4A3 and neighboring genes in ten tumor samples and three normal parotid gland samples, with only NR4A3 showing a significant upregulation (deSeq247; ***P < 0.001; Box-plot center line: median; bounds of box: 25 and 75% quantiles; whiskers: minimum and maximum values). Haller et al. 2019 Nat Commun, 10(1):368.
We discovered NAB2-STAT6 fusion genes as drivers in lipomatous solitary fibrous tumors (Barthelmess et al., 2014 Am J Pathol, 184(4):1209-18). More recently, we went further into the molecular mechanisms associated this fusion event (Bieg et al. 2021 Am J Pathol, 191(4):602-17; Haller et al. 2021 Am J Pathol, 191(7):1314-24). Within a large sequencing study, carried out with the Charité and University Clinics Ulm, we discovered specific genomic as well as transcriptional alterations that drive primary CNS lymphoma and distinguish this entity from other B-cell lymphomas (Radke et al. 2022, Nat Commun, 13:2558).
Genomic drivers in KRAS- and BRAF-mutant MSS vs. MSI colorectal carcinoma
DKFZ has engaged with the Athens Comprehensive Cancer Center (Alex Pintzas, Olga Papadodima of the National Hellenic Research Foundation; Georgios Zografos of the Gennimatas General Hospital) in the frame of a Helmholtz European Partnering. Within this collaboration, we focus on the biology of colorectal cancer, where the microsatellite status (MSI vs. MSS) is a major determinant for therapy decision. We performed WES and RNA-seq with tumors from Greek CRC patients and did integrative analysis also in combination with TCGA and CPTAC CRC data, revealing the interplay of MSI/MSS with KRAS/BRAF mutation status and of affected signaling pathways as well as transcription factors.
While our focus is mostly on colorectal carcinoma in this collaboration, we have collaborated with ACCC groups also in related projects (Mitra et al. 2021 Int J Cancer, 148(8):1993-2009; Berdiel-Acer et al. 2021 Oncogene, 40(15):2651-2666; Koralli et al. 2021 Mater Chem Front, 5(13):4950-4962).
Collaborations
Sarcoma/carcinoma: Florian Haller, Abbas Agaimy, Arndt Hartmann (Erlangen)
Breast cancer: Martina Vetter, Eva Kantelhardt, Christoph Thomssen (Halle/Saale), Christel Herold-Mende, Andreas Schneeweiss, Clarissa Gerhäuser (Heidelberg), Jens Timmer (Freiburg), Tim Beissbarth (Göttingen)
Primary CNS Lymphoma: Christel Herold-Mende (Heidelberg), Josefine Radke, Naveed Ishaque, Frank Heppner (Berlin)
ACCC: Olga Papadodima, Christos Chochos, Alex Pintzas, Georgios Zografos (Athens)
NCT-MASTER: Stefan Fröhling, Hanno Glimm (Heidelberg/Dresden)
DKFZ Proteomics Core Facility: Dominic Helm (Heidelberg)
DKFZ NGS Core Facility: Stephan Wolf (Heidelberg)