CC BY-NC-ND 4.0 · Laryngorhinootologie 2020; 99(S 02): S131-S132
DOI: 10.1055/s-0040-1710927
Abstracts
Oncology

Ex-vivo slice cultures of tumor tissues confirm the DNA double-strand break repair defect of HPV-positive OPSCC and suggest a defect in the ATM-mediated DNA damage response

Henrike Barbara Zech
1   Universitätsklinikum Hamburg Eppendorf, Klinik für Hals-Nasen-Ohrenheilkunde, Hamburg
,
CS Betz
1   Universitätsklinikum Hamburg Eppendorf, Klinik für Hals-Nasen-Ohrenheilkunde, Hamburg
,
M Kriegs
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
,
S Köcher
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
,
W Mansour
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
,
N Möckelmann
1   Universitätsklinikum Hamburg Eppendorf, Klinik für Hals-Nasen-Ohrenheilkunde, Hamburg
,
A Böttcher
1   Universitätsklinikum Hamburg Eppendorf, Klinik für Hals-Nasen-Ohrenheilkunde, Hamburg
,
Chia-Jung Busch
1   Universitätsklinikum Hamburg Eppendorf, Klinik für Hals-Nasen-Ohrenheilkunde, Hamburg
,
C Petersen
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
,
K Rothkamm
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
,
T Rieckmann
2   Universitätsklinikum Hamburg Eppendorf, Labor für Radiobiologie und Radioonkologie, Hamburg
› Author Affiliations
 

HPV-induced (HPV+) OPSCC are more sensitive towards radiation than HPV-negative. Underlying mechanism are discussed controversial, theories are enhanced cellular radiosensitivity based on a defect in DNA double-strand break (DSB) repair or stronger immunogenicity. Limitation for the first theory is the experimental restriction to a low number of HPV+ HNSCC cell lines. We assessed DSB repair of HPV+ and HPV- HNSCC using 400µm thick, patient derived tumor slice cultures, which were irradiated and fixed after 24h. Residual DSBs were analyzed by quantification of 53BP1 repair foci in enlarged, p63-positive nuclei indicative of tumor cell origin. Nuclei of HPV+ OPSCC cultures (n = 5) displayed on average a more than 5 times higher residual foci number than HPV- OPSCC (n = 5) (average foci/cell: 6.5 vs. 1.1, p<0.01; counted nuclei in total: 750). Laryngeal SCC cultures so far displayed a mean of 2.4 residual foci/cell (n = 2). Inhibition of the central DNA damage response kinase ATM resulted in a profound increase in residual foci in HPV- samples but had a clearly reduced effect in HPV+ ones. In line with this, HPV+ HNSCC cell lines showed a lower ATMi-related radiosensitization than HPV- (average dose enhancement ratio 3.24 vs. 2.11) and also less effect on residual DSBs. Our ex-vivo data, to the best of our knowledge, represent the first experimental evidence for the DSB repair defect of HPV+ OPSCC outside of established cell lines and together with cell line derived data demonstrate a defect in the ATM-mediated DNA damage response as a contributing factor. Clinically, the functional ex-vivo assay may be a powerful tool to predict individual radiosensitivity e.g. to identify the rare cases of HPV+ tumors with a functional DSB repair to be excluded from de-intensification.

Poster-PDF A-1875.PDF



Publication History

Article published online:
10 June 2020

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