HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity

Rieckmann, Thorsten; Tribius, Silke; Grob, Tobias; Meyer, Felix; Busch, Chia‐Jung; Petersen, Cordula; Dikomey, Ekkehard; Kriegs, Malte

doi:10.1016/j.radonc.2013.03.013

Cited by 277 publications

(295 citation statements)

References 25 publications

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“…Recent clinical trials have revealed that patients with HPV-infected tumors show markedly improved treatment response to conventional therapy and have a better prognosis compared with patients with HPVnegative HNSCC (3,8). Although recent studies showed that HPV-positive HNSCC cells are more sensitive to ionizing radiation (11,12), the molecular mechanism and the function of p16INK4a in the enhanced sensitivity to ionizing radiation of these tumors remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination-mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy. Cancer Res; 74(6);

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Section: Introductionmentioning

confidence: 99%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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“…[8][9][10] An increased sensitivity of HPV-positive tumor cells towards irradiation and chemotherapeutic agents was also observed in vitro and in animal studies. [11][12][13] However, as the detection rate of HPV DNA in anal SCC commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response and long-term outcome is challenging. In patients with cervical cancer, Kim et al recently reported that the semi-quantitatively measured HPV DNA load was a strong independent prognostic factor for diseasefree survival after radical RT.…”

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confidence: 99%

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

et al. 2014

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As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffinembedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load ( /> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16 INK4a were evaluated for any correlation with HPV16 DNA load and were included in uni-and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31,35,39,44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16 INK4a expression (p 5 0.001). Patients with HPV16 DNA load median and low p16 INK4a expression showed significantly worse local control (HPV16 DNA load: univariate p 5 0.023, multivariate p 5 0.042; p16 INK4a : univariate p 5 0.021), and OS (HPV16 DNA load: univariate p 5 0.02, multivariate p 5 0.03). Moreover, a combined HPV16 DNA load and p16 INK4a variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p 5 0.019, p 5 0.04 and p 5 0.031). In conclusion, these data indicate that HPV16 DNA load and p16 INK4a expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.The majority of anal squamous cell carcinoma (SCC) is considered to originate from infection with human papilloma viruses (HPV). 1,2 Especially the role of high-risk oncogenic HPV types, most prominently HPV type 16 (HPV16), in the etiology of anal SCC is well established by a multitude of epidemiological and experimental investigations. 3,4 As a consequence, technologies for the detection of HPV DNA may constitute valuable screening tools for anal malignancies and are of important clinical relevance, especially after the development of a preventive vaccine for both men and women. 5 Depending on the method used, the prevalence of HPV DNA in anal carcinoma ranges from 75% to 100% with HPV16 (>75%) and less frequent HPV18 (<10%) detection in the majority of cases. 6,7 In clinical series of head and neck as well as cervical SCC, recent data indicate that treatment response to radiotherapy (RT) or chemoradiotherapy (CRT) is superior in HPV-positive tumors as compared with their HPV-negative counterparts. [8][9][10] An increased sensitivity of HPV-positive tumor cells towards irradiation and chemotherapeutic agents was also observed in vitro and in animal studies. [11][12][13] However, as the detection rate of HPV DNA in anal SCC commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment respon...

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“…A large number of studies have proven that head and neck cancers that are positive for HPV have higher cellular radiosensitivity than their non-HPV counterparts [74,75]. One of the explanations for this behaviour is the impaired DNA repair ability found among HPV-positive tumours and a considerable G 2 arrest.…”

Section: One Of the Known Risk Factors In Head And Neck Cancer Is Thementioning

confidence: 99%

“…This unusual behaviour alters the expected cellular distribution along the cell cycle, accumulating the HPV cells in the more radiosensitive phases. Therefore, patients that tested positive for HPV respond better to the effect of radiotherapy and have a more favourable prognosis than non-HPV patients [74].…”

Section: One Of the Known Risk Factors In Head And Neck Cancer Is Thementioning

confidence: 99%

“…Thus, the HPV status of the tumour could be regarded as a strong and independent prognostic factor for the success of the treatment, both in terms of local regional control and overall survival. This is due the increased cellular radiosensitivity caused by compromised DNA repair capacity in HPV-positive cells [74]. This might indicate that radiosensitivity and repair in cells should be correlated.…”

Section: Radiosensitivitymentioning

confidence: 99%

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HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity

Cited by 277 publications

References 25 publications

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

The Six Rs of Head and Neck Cancer Radiotherapy

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HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity

Cited by 277 publications

References 25 publications

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

Human papillomavirus DNA load and p16INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

The Six Rs of Head and Neck Cancer Radiotherapy

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Product

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Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy