DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients
Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/6/1194 |
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| author | Ioan T. Bold Ann-Kathrin Specht Conrad F. Droste Alexandra Zielinski Felix Meyer Till S. Clauditz Adrian Münscher Stefan Werner Kai Rothkamm Cordula Petersen Kerstin Borgmann |
| author_facet | Ioan T. Bold Ann-Kathrin Specht Conrad F. Droste Alexandra Zielinski Felix Meyer Till S. Clauditz Adrian Münscher Stefan Werner Kai Rothkamm Cordula Petersen Kerstin Borgmann |
| author_sort | Ioan T. Bold |
| collection | DOAJ |
| description | Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (<i>p</i> = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades. |
| first_indexed | 2024-03-10T13:23:26Z |
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| id | doaj.art-a59242ed03604c2f858d115d3ee3de5d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:23:26Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a59242ed03604c2f858d115d3ee3de5d2023-11-21T09:51:40ZengMDPI AGCancers2072-66942021-03-01136119410.3390/cancers13061194DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC PatientsIoan T. Bold0Ann-Kathrin Specht1Conrad F. Droste2Alexandra Zielinski3Felix Meyer4Till S. Clauditz5Adrian Münscher6Stefan Werner7Kai Rothkamm8Cordula Petersen9Kerstin Borgmann10Laboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyLaboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyUniversity Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyLaboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyLaboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Tumorbiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyLaboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyLaboratory of Radiobiology & Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyAneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (<i>p</i> = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades.https://www.mdpi.com/2072-6694/13/6/1194chromosomal instability (CIN)CIN70 scorereplication stressChk1 inhibitionHNSCCradiotherapy |
| spellingShingle | Ioan T. Bold Ann-Kathrin Specht Conrad F. Droste Alexandra Zielinski Felix Meyer Till S. Clauditz Adrian Münscher Stefan Werner Kai Rothkamm Cordula Petersen Kerstin Borgmann DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients Cancers chromosomal instability (CIN) CIN70 score replication stress Chk1 inhibition HNSCC radiotherapy |
| title | DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients |
| title_full | DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients |
| title_fullStr | DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients |
| title_full_unstemmed | DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients |
| title_short | DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients |
| title_sort | dna damage response during replication correlates with cin70 score and determines survival in hnscc patients |
| topic | chromosomal instability (CIN) CIN70 score replication stress Chk1 inhibition HNSCC radiotherapy |
| url | https://www.mdpi.com/2072-6694/13/6/1194 |
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