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March 2019 - Johannes Längle

Dr. Johannes Längle

MedUni Wien RESEARCHER OF THE MONTH March 2019

Colorectal liver metastases: DNA damage could predict prognosis and response to therapy

Colorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of cancer mortality in women and men worldwide [1]. Half of those patients affected with CRC will develop liver metastases (CLM) over time [2]. Currently only 30% of these patients can be cured [3]. This calls for the urgent need to develop new markers to better predict prognosis and treatment response.

Studies on cell lines and animal models revealed that DNA damage of tumor cells can lead to type I interferon (IFN) induction [4]. Type I IFN is a signaling molecule, which is essential for the induction of cytotoxic T lymphocytes [5]. These immune cells are further capable to target the tumor cells and thereby improving the chances to overcoming the disease [6].

Our work disproves the results of the preclinical studies and demonstrates that DNA damage has a negative impact on recurrence-free and overall survival [7]. She even points out that patients with CLM, which show high DNA damage, represent a high-risk group. This study highlights the importance of translating data obtained in preclinical studies to a clinically setting. Nevertheless, this translation should still be examined in larger cohorts, as well as in different disease stages and cancers.

This study makes a significant contribution to the advancement of precision medicine, as markers for these strand breaks could serve as prognostic and/or predictive biomarker for therapy treatment. Recently, a positron emission tomography (PET) marker for DNA damage has been developed [8], which could serve for the evaluation of treatment response and/or prediction of clinical prognosis during the course of the disease.

Selected Literature

1. Laengle J, Stift J, Bilecz A, Wolf B, Beer A, Hegedus B, et al. DNA damage predicts prognosis and treatment response in colorectal liver metastases superior to immunogenic cell death and T cells. Theranostics. 2018;8:3198–213.

2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–86.

3. Desch CE, Benson AB, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, et al. Colorectal cancer surveillance: 2005 Update of an American Society of Clinical Oncology practice guideline. J. Clin. Oncol. 2005;23:8512–9.

4. Cummings LC, Payes JD, Cooper GS. Survival after hepatic resection in metastatic colorectal cancer: A population-based study. Cancer. 2007;109:718–26.

5. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MYK, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41:830–42.

6. Fuertes MB, Kacha  a. K, Kline J, Woo S-R, Kranz DM, Murphy KM, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8 + dendritic cells. J. Exp. Med. 2011;208:2005–16.

7. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:1–12.

8. Knight JC, Mosley MJ, Bravo LC, Kersemans V, Allen PD, Mukherjee S, et al. 89Zr-anti-gH2AX-TAT but not18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 2017;23:6498–504.

9. Petricevic B*, Laengle J*, Singer J, Sachet M, Fazekas J, Steger G, et al. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients. J. Transl. Med. 2013;11:307.

10. Weiss R*, Laengle J*, Sachet M, Shurygina A-P, Kiselev O, Egorov A, et al. Interleukin-24 inhibits influenza A virus replication in vitro through induction of toll-like receptor 3 dependent apoptosis. Antiviral Res. 2015;123:93–104.

11. Hock K*, Laengle J*, Kuznetsova I, Egorov A, Hegedus B, Dome B, et al. Oncolytic influenza A virus expressing interleukin-15 decreases tumor growth in vivo. Surgery. 2017;161:735–46.

12. Rieder FJJ, Gröschel C, Kastner M-T, Kosulin K, Laengle J, Zadnikar R, et al. Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells. J. Steroid Biochem. Mol. Biol. Elsevier Ltd; 2017;165:356–362.

13. Thannesberger J, Hellinger HJ, Klymiuk I, Kastner MT, Rieder FJJ, Schneider M,  Fister S, Lion T, Kosulin K, Laengle J et al. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples. FASEB J. 2017;31:1987–2000.

14. Miller A, Nagy C, Knapp B, Laengle J, Ponweiser E, Groeger M, et al. Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments. Cell Metab. 2017;26:788–800.

15. Schweiger T, Liebmann-Reindl S, Glueck O, Starlinger P, Laengle J, Birner P, et al. Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery. J. Thorac. Dis. 2018;10:6147–57.

*Contributed equally


Dr.med.univ. Johannes Längle

Medizinische Universität Wien
Universitätsklinik für Chirurgie
Klinische Abteilung für Allgemeinchirurgie
Währinger Gürtel 18-20
1090 Wien

T: +43 1 40400 73525, 72470
F: +43 1 40400 73593
johannes.laengle@meduniwien.ac.at
www.meduniwien.ac.at/chirurgie