AG Functional Genomics
Head: Prof. Dr. rer. nat. Doris Steinemann
"Not every variant in the genome is clinically relevant. We have to learn to separate neutral from pathogenic variants from the large number of genetic changes. Bioinformatics will therefore play a decisive role not only in the evaluation of the enormous amounts of data, but also in the subsequent interpretation of the gene variants." Doris Steinemann
Staff members
- Doris Steinemann, Prof. Dr. rer. nat., specialist human geneticist, Director
- Winfried Hofmann, Dr. rer. nat., research associate, bioinformatics, deputy team leader
- Lena Wendeburg, Dipl. Biotechnologist (FH)
- Bernardus Aldrige Allister, Dr. rer. nat. Collaborator in the project: "Regulatory Variants in Hereditary Breast and Ovarian Cancer" funded by the DFG
- Isabel Klefenz, Dr. med., Ph.D. student in the project "Suscebtibilitiy to Immunodeficiencies" funded by RESIST and MHH HBRS
- Robert Fietz, cand. Dr. med., StrucMed
- Philipp Hermann Benjamin Knopf, cand. Dr. med.
- Erfan Rezaei Gharehbolagh, cand. Dr. med.
- Linus Maximilian Laaff, Medical Technologist Laboratory Analysis
Former research associates:
- Dr. rer. nat. Jonathan Lukas Lühmann
- Dr. rer. nat. Rensheng Wan
- Dr. med. Leonie Braun, StrucMed
- Dr. med. Jan Hendrik Niemann, StrucMed
- Gina Kastens, M. Sc. Biomedicine
- Dr. rer. nat. Janin Anna Klein (née Bublitz), Ph.D. in Molecular Medicine
- Dr. rer. nat. Maximilian Schieck, PostDoc
- Dr. rer. nat. Jana Lisa van Luttikhuizen, Ph.D. in Molecular Medicine
- Dr. med. Mareike Jung, StrucMed
- Dr. med. Judith Penkert, StrucMed
- Marie Stelter, M. Sc. in Biomedicine
- Dr. Dr. rer. nat. Stephanie Schubert, PostDoc
- Dr. rer. nat. Lisa Pahl, PostDoc
- Dr. rer. nat. Sonja Hänzelmann, PostDoc
- Cassandra Winter, M. Sc. Biochemistry
- Anthony Petkidis, B.Sc. Biochemistry
- Dr. rer. nat. Georgi Manukjan, Ph.D. in Molecular Medicine
- Dr. med. Tim Ripperger, Ph.D. in Molecular Medicine
- Dr. med. Simone Feurstein, StrucMed
Our research objective
Our aim is to identify changes in the genome and to understand their significance with regard to the development of a disease. To detect intronic and structural variants, we use state-of-the-art molecular genetic techniques such as genome sequencing and optical genome mapping (OGM; https://bionanogenomics.com), which enables the de novo assembly of genomes. In particular, structural genome variants ranging in size from 50 bp to several Mb can have a major impact on the expression of genes in the affected or nearby region and cause gene products and cell functions to go out of control. Knowledge of disturbed processes in the cell can enable a derived and targeted therapy and represents an important step on the way to curing patients.
Main areas of research:
In families with a high incidence of breast and ovarian cancer (HBOC), a clear molecular genetic diagnosis can be made in around 20% of cases, from which therapeutic consequences can be derived. The diagnosis is limited to the protein-coding sequences of consortially coordinated and internationally established nuclear genes(ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, RAD51C, RAD51D, TP53). However, changes outside these gene-coding sequence segments can also be relevant and lead to the inactivation of products of the same risk genes. These should be detected by genome sequencing and OGM in highly selected families. Experience has shown that a large number of changes are found in individuals whose functional significance with regard to a possible dysregulation of cellular processes is unclear. Prediction programs, in silico analyses and databases of large sequencing projects help us to interpret pathogenicity.
Collaborations: The Functional Genomics team cooperates intensively with national and international consortia to compare the frequency of gene variants in large case/control groups and on a population basis (e.g. German Hereditary Breast and Ovarian Cancer Consortium, www.konsortium-familiaerer-brustkrebs.de). There is also close cooperation at the MHH (pathology, gynecological oncology) with regard to somatic changes in the tumors.
In this project, we want to better understand the genetic basis of congenital immunodeficiencies. While it is no problem for most people or their immune system to cope with viral or bacterial pathogens, to attack them and eliminate them quickly, there are others who are extremely susceptible and have to deal with a severe course. This can have a variety of genetic causes. Almost 500 genes are known to be involved in dysregulation of the immune system. Nevertheless, even after whole exome sequencing, many patients remain undiagnosed. This is due to the fact that, in the past, SNPs rather than structural genome variants were targeted. Together with other scientists in RESIST, who have collected or will collect large cohorts of corresponding patients, we want to investigate the significance of larger genomic rearrangements with regard to the immune response.
https://www.resist-cluster.de/forschung/projektbereich-a-gene/projekt-a2/
Structural variants are also of central importance for the stratification of childhood leukemias. For example, they can lead to gene fusions and activate oncogenes constitutively. ABL kinase and other kinase gene fusions in particular have become increasingly important in recent years. The Functional Genomics team is one of the first research institutions in Europe to use OGM technology from Bionano Genomics(https://bionanogenomics.com/). This enables high-resolution de novo mapping of the genome and is a suitable method for identifying prognostically and therapeutically relevant structural changes. Aneuploidies, copy number changes, translocations, inversions and insertions are detected with high sensitivity and specificity using this method. It has been shown that many of the chromosomal alterations are significantly more complex than they initially appear with other methods and that cryptic alterations in particular can be resolved very well.
Publication list 2020 - today
2022
Sandmann S, Behrens YL, Davenport C, Thol F, Heuser M, Dörfel D, Löhr F, Castrup A, Steinemann D, Varghese J, Schlegelberger B, Dugas M, Göhring G. Clonal Evolution at First Sight: A Combined Visualization of Diverse Diagnostic Methods Improves Understanding of Leukemic Progression. Front Oncol. 2022 Jul 8;12:888114. doi: 10.3389/fonc.2022.888114. PMID: 35875134; PMCID: PMC9305660.
Suttorp J, Lühmann JL, Behrens YL, Göhring G, Steinemann D, Reinhardt D, Neuhoff NV, Schneider M. Optical Genome Mapping as a Diagnostic Tool in Pediatric Acute Myeloid Leukemia. Cancers (Basel). 2022 Apr 19;14(9):2058. doi: 10.3390/cancers14092058. PMID: 35565187; PMCID: PMC9102001.
Wan R, Schieck M, Caballero-Oteyza A, Hofmann W, Cochino AV, Shcherbina A, Sherkat R, Wache-Mainier C, Fernandez A, Sultan M, Illig T, Grimbacher B, Proietti M, Steinemann D. Copy Number Analysis in a Large Cohort Suggestive of Inborn Errors of Immunity Indicates a Wide Spectrum of Relevant Chromosomal Losses and Gains. J Clin Immunol. 2022 Apr 29. doi: 10.1007/s10875-022-01276-8. Epub ahead of print. PMID: 35486341.
Ghandili S, Kluger MA, Leitner T, Grahammer F, Kirchner L, Modemann F, Achilles EG, Kreipe HH, Klein J, Steinemann D, Wolschke C, Fischer L, Bokemeyer C, Fiedler W, Huber TB, Alsdorf WH, Mahmud M. Donor-transmitted extramedullary acute myeloid leukaemia after living donor kidney transplantation. Br J Haematol. 2022 Jul;198(1):199-202. doi: 10.1111/bjh.18194. Epub 2022 Apr 15. PMID: 35428972; PMCID: PMC9321064.
2021
Eggenschwiler R, Gschwendtberger T, Felski C, Jahn C, Langer F, Sterneckert J, Hermann A, Lühmann J, Steinemann D, Haase A, Martin U, Petri S, Cantz T. A selectable all-in-one CRISPR prime editing piggyBac transposon allows for highly efficient gene editing in human cell lines. Sci Rep. 2021 Nov 12;11(1):22154. doi: 10.1038/s41598-021-01689-2. PMID: 34773059; PMCID: PMC8589839.
Lühmann JL, Stelter M, Wolter M, Kater J, Lentes J, Bergmann AK, Schieck M, Göhring G, Möricke A, Cario G, Žaliová M, Schrappe M, Schlegelberger B, Stanulla M, Steinemann D. The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia. Cancers (Basel). 2021 Aug 30;13(17):4388. doi: 10.3390/cancers13174388. PMID: 34503197; PMCID: PMC8431583.
Salim M, Heldt F, Thomay K, Lentes J, Behrens YL, Kaune B, Möricke A, Cario G, Schieck M, Hofmann W, Davenport C, Steinemann D, Schrappe M, Schlegelberger B, Göhring G. Cryptic TCF3 fusions in childhood leukemia: Detection by RNA sequencing. Genes Chromosomes Cancer. 2022 Jan;61(1):22-26. doi: 10.1002/gcc.22998. Epub 2021 Sep 13. PMID: 34460133.
Dannenmann B, Klimiankou M, Oswald B, Solovyeva A, Mardan J, Nasri M, Ritter M, Zahabi A, Arreba-Tutusaus P, Mir P, Stein F, Kandabarau S, Lachmann N, Moritz T, Morishima T, Konantz M, Lengerke C, Ripperger T, Steinemann D, Erlacher M, Niemeyer CM, Zeidler C, Welte K, Skokowa J. iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia. Cell Stem Cell. 2021 May 6;28(5):906-922.e6. doi: 10.1016/j.stem.2021.03.023. Epub 2021 Apr 23. PMID: 33894142.
Hoffmann D, Sens J, Brennig S, Brand D, Philipp F, Vollmer Barbosa P, Kuehle J, Steinemann D, Lenz D, Buchegger T, Morgan M, Falk CS, Klein C, Lachmann N, Schambach A. Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages. J Pers Med. 2021 Mar 20;11(3):221. doi: 10.3390/jpm11030221. PMID: 33804706; PMCID: PMC8003874.
Decker M, Lammens T, Ferster A, Erlacher M, Yoshimi A, Niemeyer CM, Ernst MPT, Raaijmakers MHGP, Duployez N, Flaum A, Steinemann D, Schlegelberger B, Illig T, Ripperger T. Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies. Leukemia. 2021 Nov;35(11):3304-3308. doi: 10.1038/s41375-021-01200-w. Epub 2021 Mar 10. PMID: 33692461; PMCID: PMC8550979.
Behrens YL, Schienke A, Davenport C, Lentes J, Tauscher M, Steinemann D, Rasche M, Knirsch S, Joachim S, Reinhardt D, Schlegelberger B, Göhring G. BCR-ABL1 positive AML or CML in blast crisis? A pediatric case report with inv(3) and t(9;22) in the initial clone. Cancer Genet. 2021 Jun;254-255:70-74. doi: 10.1016/j.cancergen.2021.02.007. Epub 2021 Feb 19. PMID: 33647814.
Winter G, Kirschner-Schwabe R, Groeneveld-Krentz S, Escherich G, Möricke A, von Stackelberg A, Stanulla M, Bailey S, Richter L, Steinemann D, Ripperger T, Escudero A, Farah R, Lohi O, Wadt K, Jongmans M, van Engelen N, Eckert C, Kratz CP. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li-Fraumeni syndrome. Leukemia. 2021 May;35(5):1475-1479. doi: 10.1038/s41375-021-01163-y. Epub 2021 Feb 12. PMID: 33580201; PMCID: PMC8102191.
Kirchhoff H, Karsli U, Schoenherr C, Battmer K, Erschow S, Talbot SR, Steinemann D, Heuser M, Heidenreich O, Hilfiker-Kleiner D, Ganser A, Eder M, Scherr M. Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL. Blood. 2021 May 13;137(19):2657-2661. doi: 10.1182/blood.2020008544. PMID: 33512436.
Warnstorf D, Bawadi R, Schienke A, Strasser R, Schmidt G, Illig T, Tauscher M, Thol F, Heuser M, Steinemann D, Davenport C, Schlegelberger B, Behrens YL, Göhring G. Unbalanced translocation der(5;17) resulting in a TP53 loss as recurrent aberration in myelodysplastic syndrome and acute myeloid leukemia with complex karyotype. Genes Chromosomes Cancer. 2021 Jun;60(6):452-457. doi: 10.1002/gcc.22938. Epub 2021 Feb 19. PMID: 33486841.
Schwab C, Roberts K, Boer JM, Göhring G, Steinemann D, Vora A, Macartney C, Hough R, Thorn Z, Dillon R, Escherich G, Cazzaniga G, Schlegelberger B, Loh M, den Boer ML, Moorman AV, Harrison CJ. SSBP2-CSF1R is a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome. Blood. 2021 Apr 1;137(13):1835-1838. doi: 10.1182/blood.2020008536. PMID: 33197935.
2020
Cullmann K, Jahn M, Spindler M, Schenk F, Manukjan G, Mucci A, Steinemann D, Boller K, Schulze H, Bender M, Moritz T, Modlich U. Forming megakaryocytes from murine-induced pluripotent stem cells by the inducible overexpression of supporting factors. Res Pract Thromb Haemost. 2020 Dec 3;5(1):111-124. doi: 10.1002/rth2.12453. PMID: 33537535; PMCID: PMC7845061.
Radner M, van Luttikhuizen JL, Bartels S, Bublitz J, Grote I, Rieger L, Christgen H, Stark H, Werlein C, Lafos M, Steinemann D, Lehmann U, Christgen M, Kreipe H. Chromosome 2q gain and epigenetic silencing of GATA3 in microglandular adenosis of the breast. J Pathol Clin Res. 2021 May;7(3):220-232. doi: 10.1002/cjp2.195. Epub 2020 Dec 31. PMID: 33382535; PMCID: PMC8073017.
Barnes DR, Rookus MA, ... , Steinemann D, ..., Easton Dr., Chenevix-Trench G, Antoniou AC; Consortium of Investigators of Modifiers of BRCA and BRCA2. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020 Oct;22(10):1653-1666. doi: 10.1038/s41436-020-0862-x. Epub 2020 Jul 15. PMID: 32665703; PMCID: PMC7521995.
Niemann JH, Du C, Morlot S, Schmidt G, Auber B, Kaune B, Göhring G, Ripperger T, Schlegelberger B, Hofmann W, Smol T, Ait-Yahya E, Raimbault A, Lambilliotte A, Petit F, Steinemann D. De novo missense variants in the RAP1B gene identified in two patients with syndromic thrombocytopenia. Clin Genet. 2020 Oct;98(4):374-378. doi: 10.1111/cge.13807. Epub 2020 Jul 21. PMID: 32627184.
Jung M, Schieck M, Hofmann W, Tauscher M, Lentes J, Bergmann A, Stelter M, Möricke A, Alten J, Schlegelberger B, Schrappe M, Zimmermann M, Stanulla M, Cario G, Steinemann D. Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP-BFM acute lymphoblastic leukemia protocol. Genes Chromosomes Cancer. 2020 Nov;59(11):667-671. doi: 10.1002/gcc.22882. Epub 2020 Jul 7. PMID: 32592278; PMCID: PMC7540392.
Christgen M, Bartels S, van Luttikhuizen JL, Bublitz J, Rieger LU, Christgen H, Stark H, Sander B, Lehmann U, Steinemann D, Derksen PWB, Kreipe H. E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements. Mod Pathol. 2020 Dec;33(12):2483-2498. doi: 10.1038/s41379-020-0591-3. Epub 2020 Jun 22. PMID: 32572153; PMCID: PMC7685979.
Kalasova I, Hailstone R, Bublitz J, Bogantes J, Hofmann W, Leal A, Hanzlikova H, Caldecott KW. Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair. Nucleic Acids Research, Volume 48, Issue 12, July 09, 2020, 6672-6684. doi: 10.1093/nar/gkaa489. Epub 2020 June 06. PMID: 32504494; PMCID: PMC7337934
Rio-Machin A, Vulliamy T,... Schlegelberger B, Ripperger T, Steinemann D,... Fitzgibbon J, Dokal I. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat Commun. 2020 Feb 25;11(1):1044. doi: 10.1038/s41467-020-14829-5. PMID: 32098966; PMCID: PMC7042299.
Schieck M, Lentes J, Thomay K, Hofmann W, Behrens YL, Hagedorn M, Ebersold J, Davenport CF, Fazio G, Möricke A, Buchmann S, Alten J, Cario G, Schrappe M, Bergmann AK, Stanulla M, Steinemann D, Schlegelberger B, Cazzaniga G, Göhring G. Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia. Ann Hematol. 2020 Apr;99(4):809-818. doi: 10.1007/s00277-020-03953-3. Epub 2020 Feb 20. PMID: 32078009; PMCID: PMC7069912.
Fuchs NV, Schieck M, Neuenkirch M, Tondera C, Schmitz H, Wendeburg L, Steinemann D, Elpers C, Rutsch F, König R. Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi-Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1). Stem Cell Res. 2020 Mar;43:101697. doi: 10.1016/j.scr.2019.101697. Epub 2020 Jan 9. PMID: 32062129.
Hoffmann D, Kuehle J, Lenz D, Philipp F, Zychlinski D, Lachmann N, Moritz T, Steinemann D, Morgan M, Skokowa J, Klein C, Schambach A. Lentiviral gene therapy and vitamin B3 treatment enable granulocytic differentiation of G6PC3-deficient induced pluripotent stem cells. Gene Ther. 2020 Jun;27(6):297-306. doi: 10.1038/s41434-020-0127-y. Epub 2020 Feb 12. PMID: 32051561.
Fuchs NV, Schieck M, Neuenkirch M, Tondera C, Schmitz H, Steinemann D, Göhring G, König R. Induced pluripotent stem cell line (PEIi003-A) derived from an apparently healthy male individual. Stem Cell Res. 2020 Jan;42:101679. doi: 10.1016/j.scr.2019.101679. Epub 2019 Dec 4. PMID: 31837633.
van Luttikhuizen JL, Bublitz J, Schubert S, Schmidt G, Hofmann W, Morlot S, Buurman R, Auber B, Schlegelberger B, Steinemann D. From a variant of unknown significance to pathogenic: Reclassification of a large novel duplication in BRCA2 by high-throughput sequencing. Mol Genet Genomic Med. 2020 Sep;8(9):e1045. doi: 10.1002/mgg3.1045. Epub 2019 Nov 13. PMID: 31724318; PMCID: PMC7506983.
Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, Cazzaniga G, Fazio G, Sutton R, Elitzur S, Izraeli S, Lauten M, Locatelli F, Basso G, Buldini B, Bergmann AK, Lentes J, Steinemann D, Göhring G, Schlegelberger B, Haas OA, Schewe D, Buchmann S, Moericke A, White D, Revesz T, Stanulla M, Mann G, Bodmer N, Arad-Cohen N, Zuna J, Valsecchi MG, Zimmermann M, Schrappe M, Biondi A. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica. 2020 Jul;105(7):1887-1894. doi: 10.3324/haematol.2019.231720. Epub 2019 Oct 10. PMID: 31601692; PMCID: PMC7327633