DNA damage & Cancer

Dysfunction of the DNA damage response is a driving force for genome instability and cancer. In childhood cancers, inherited mutations in cancer predisposition genes substantially contribute to cancer development and was linked to specific cancer-predisposing syndromes (CPS). Numerous CPS including Li-Fraumeni syndrome (LFS), Li-Fraumeni like syndrome (LFLS) and Fanconi anemia (FA)/Breast Cancer Associated (BRCA) have been described. In general, LFS and LFLS patients harbor germline mutations in genes regulating the tumor suppressor p53 pathway, while FA/BRCA patients harbor mutations in genes required for DNA double-strand break (DSB) repair. Interestingly, a substantial part of FA, LFS and LFLS patients do not harbor the known homozygous mutations in the genes linked to the respective CPS. Consequently, the mechanisms driving the CPS in those patients remain unclear. In this collaborative project, we used whole-exome sequencing (WES) of parents-children trios to identify germline mutations in children with cancer. Our bioinformatic analysis revealed a set of novel combined heterozygous mutations in the FA/BRCA and the LFS/LFLS pathway as well as in genes coding for the DNA damage signaling kinases ATM, ATR and HIPK2 in the germline of children with cancer.

Research website

Positions Held

Since 2018: W3-Professor & Chair of Toxicology, Institute of Toxicology, University Medical Center at the University of Mainz. Director, Institute of Toxicology, University Medical Center at the University of Mainz
2008 - 2018: Permanent Group Leader Position, DKFZ, Heidelberg
2006 - 2018: Head of Research Group “Cellular Senescence”, German Cancer Research Center (DKFZ), Heidelberg
2004 - 2005: Research Group “Molecular Ageing Research”, German Center for Research on Ageing (DZFA), University of Heidelberg

Education

2016: Habilitation and venia legendi for Biochemistry & Molecular Biology , Faculty of Biology, 
University of Heidelberg 
2000 - 2004: Postdoctoral research with Prof. Hans Will, Heinrich-Pette-Institut, University of Hamburg
2000: PhD (summa cum laude), University of Heidelberg
1997 - 2000: PhD studies with Prof. Wulf Dröge, DKFZ Heidelberg
1997: Diploma in Biology, University of Heidelberg
1991 - 1997: Studies of Biology, University of Heidelberg

Selected publications by Thomas Hofmann:

Rodríguez-Paredes M, Bormann F, Raddatz G, Gutekunst J, Lucena-Porcel C, Köhler F, Wurzer E, Schmidt K, Gallinat S, Wenck H, Röwert-Huber J, Denisova E, Feuerbach L, Park J, Brors B, Herpel E, Nindl I, Hofmann TG, Winnefeld M and Lyko F (2018). Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. Nat Comm, 8: 577. doi: 10.1038/s41467-018-03025-1.

Conrad E, Polonio-Vallon T, Meister M, Matt S, Bitomsky N, Herbel C, Liebl M, Greiner V, Kriznik B, Schumacher S, Krieghoff-Henning E, and Hofmann TG (2016). HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism. Cell Death Differ, 23: 110-122. 

Ucar O, Kaiyong Li, Dvornikov D, Kreuz C, Timmer J, Matt S, Brenner L, Smedley S, Travis MA, Hofmann TG, Klingmüller U and Kyewski B (2016). A thymic epithelial stem cell pool persists throughout ontogeny and is modulated by TGF-. Cell Reports, 17, October 4.

Polonio-Vallon T, Kirkpatrick J, Krijgsveld J and Hofmann TG (2014). Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization. Cell Cycle, 13: 115-125.

Abu-Odeh M, Salah Z, Herbel C, Hofmann TG and Aqeilan RI (2014). WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. Proc Natl Acad Sci USA, 111: E4716-25

Ucar A, Ucar O, Klug P, Matt S, Brunk F, Hofmann TG* and Kyewski B* (2014). Adult thymus contains FoxN1- epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity, 41: 257-269. 

Bitomsky N, Conrad E, Moritz C, Polonio-Vallon T, Sombroek S, Schultheiss C, Glas C, Greiner V, Herbel C, Mantovani F, del Sal G, Peri F and Hofmann TG (2013). Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci USA, 110: 115-125. 

Crone J, Glas C, Schultheiss K, Moehlenbrink J, Krieghoff-Henning E and Hofmann TG (2011). Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer Res, 71: 2350-2359.

Textor S, Fiegler N, Arnold A, Porgador A, Hofmann TG and Cerwenka a (2011). Human NK cells are allerted to induction of p53 in cancer cells by upregulation oft he NKG2D ligands ULBP1 and ULBP2. Cancer Res,  71: 5998-6009.

Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J and Hofmann TG (2008). Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology, 10: 812-824. 


# shared senior & corresponding authorship