DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival

Papalouka, Chara; Adamaki, Maria; Batsaki, Panagiota; Zoumpourlis, Panagiotis; Tsintarakis, Antonis; Goulielmaki, Maria; Fortis, Sotirios P.; Baxevanis, Constantin N.; Zoumpourlis, Vassilis

doi:10.3390/ijms24032760

Cited by 13 publications

(7 citation statements)

References 238 publications

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“…DSBs trigger a DNA damage response (DDR) signaling cascade that involves a network of multiple proteins acting as sensors, transducers/mediators or effectors and comprises damage recognition, cell cycle arrest, DNA repair and cell death [5]. The MRE11-RAD50-NBS1/NBN (MRN) protein complex is responsible for initial DSB sensing, signal transduction and response to lesions and functions in both HR and NHEJ [6].…”

Section: Introductionmentioning

confidence: 99%

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients

Butkiewicz,

Krześniak,

Gdowicz-Kłosok

et al. 2023

Cancers

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Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.

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Section: Introductionmentioning

confidence: 99%

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients

Butkiewicz,

Krześniak,

Gdowicz-Kłosok

et al. 2023

Cancers

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“…NHEJ deficiency may not only be involved in NPC etiology but also have important clinical implications. Targeting the DNA repair pathway can enhance the efficacy of DNA-damaging therapy (e.g., chemotherapy and radiotherapy) [ 26 ]. In particular, radiotherapy is the primary treatment for patients with NPC, and approximately 20% of patients’ experience treatment failure due to tumor radio-resistance.…”

Section: Discussionmentioning

confidence: 99%

Non-Homologous End-Joining Pathway Genotypes Significantly Associated with Nasopharyngeal Carcinoma Susceptibility

et al. 2023

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Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype–phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 NPC patients. The results showed significant differences in the distributions of variant genotypes at XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 between the cases and controls. The variant genotypes of these three polymorphisms were associated with significantly increased NPC risks. NPC patients with the risk genotypes at XRCC6 rs2267437 had significantly reduced expression levels of both mRNA and protein, as well as a lower NHEJ repair capacity, than those with the wild-type genotype. In conclusion, XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 in the NHEJ pathway were associated with NPC susceptibility. XRCC6 rs2267437 can modulate mRNA and protein expression and the NHEJ repair capacity.

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“…The reasons for the negative influence of alcohol consumption in patients' prognosis are still unclear (Sawabe et al, 2017). However, some mechanisms might involve cell proliferation, decrease DNA‐repair machinery and impaired antioxidant defence (Papalouka et al, 2023; Ratna & Mandrekar, 2017). In particular, alcohol consumption can lead to a decrease in patients' nutrient status, which can weaken the activity of the immune system (Meadows & Zhang, 2015).…”

Section: Discussionmentioning

confidence: 99%

High‐risk TP53 mutations predict poor primary treatment response of patients with head and neck squamous cell carcinoma

et al. 2023

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ObjectivesHead and neck squamous cell carcinoma (HNSCC) poses a diagnostic and therapeutic challenge worldwide and is associated with a poor survival rate. Due to the variability in the efficacy of treatments for HNSCC, new predictive biomarkers of therapy outcomes are needed. Recently, we developed an algorithm that employs the mutational profile of TP53 as an independent prognostic factor in HNSCC. In this study, we investigated its role as a predictive biomarker of treatment outcomes in HNSCC patients. We also tested the usefulness of two classification systems for TP53 mutational landscapes.Materials and MethodsClinical and genomic data were retrieved from The Cancer Genome Atlas database. We built a multivariate stepwise backward binary regression model to assess the role of TP53 mutations in predicting therapeutic outcomes.ResultsCases harbouring high‐risk‐of‐death mutations reported an odds ratio of 3.301 for stable or progressive disease compared to wild‐type cases, while no significant difference in treatment outcomes was found between cases with low‐risk‐of‐death mutations and wild‐type TP53. Our analysis found that older patients with a history of alcohol consumption had a higher risk of stable/progressive disease.ConclusionsThis study improves current evidence on the role of TP53 mutations in treatment response in HNSCC patients.

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DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival

Cited by 13 publications

References 238 publications

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients

Non-Homologous End-Joining Pathway Genotypes Significantly Associated with Nasopharyngeal Carcinoma Susceptibility

High‐risk TP53 mutations predict poor primary treatment response of patients with head and neck squamous cell carcinoma

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