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David Sidransky - One of the best experts on this subject based on the ideXlab platform.

  • P16 mts 1 cdkn2 ink4a in cancer progression
    Experimental Cell Research, 2001
    Co-Authors: James W Rocco, David Sidransky
    Abstract:

    Abstract Since its discovery as an inhibitor of cyclin-dependent kinases 4 and 6, the tumor suppressor P16 has continued to gain widespread importance in cancer. The high frequency of deletions of P16 in tumor cell lines first suggested an important role for P16 in carcinogenesis. This initial genetic evidence was subsequently strengthened by numerous studies documenting P16 inactivation in kindreds with familial melanoma. Moreover, a high frequency of P16 gene alterations was found in primary tumors, while recent studies have identified P16 promoter methylation as a major mechanism of tumor-suppressor-gene silencing. Additional insight into P16's role in cancer has come from the genetic analysis of precancerous lesions and various tissue culture models. It is now believed that loss of P16 is an early and often critical event in tumor progression. Consequently, P16 is a major tumor-suppressor gene whose frequent loss occurs early in many human cancers.

  • role of the P16 tumor suppressor gene in cancer
    Journal of Clinical Oncology, 1998
    Co-Authors: William H Liggett, David Sidransky
    Abstract:

    Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor P16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of P16 in human cancer cell lines first suggested an important role for P16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that P16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of P16 gene alterations were observed in many primary tumors. In human neoplasms, P16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of P16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. P16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor...

Jens Overgaard - One of the best experts on this subject based on the ideXlab platform.

  • impact of hpv associated P16 expression on radiotherapy outcome in advanced oropharynx and non oropharynx cancer
    Radiotherapy and Oncology, 2014
    Co-Authors: P Lassen, Hanne Primdahl, Jorgen Johansen, Claus Kristensen, Elo Andersen, Lisbeth Juhler Andersen, Jan F Evensen, Jesper Grau Eriksen, Jens Overgaard
    Abstract:

    Background and purpose: HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/P16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPVassociated P16-expression in a cohort of patients with stage III–IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/ P16 also extends to tumors of non-oropharyngeal origin. Material and methods: 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by P16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. Results: Thirty-eight percent (490/1294) of the tumors were P16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p < .0001. In OPC P16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32–0.57]), event-free survival (EFS) (HR 0.44 [0.35–0.56]), and overall survival (OS) (HR: 0.38 [0.29–0.49]), respectively, compared with P16-negativity. In non-OPC no prognostic impact of P16-status was found for either endpoint: LRC (HR: 1.13 [0.75–1.70]), EFS (HR: 1.06 [0.76–1.47]), and OS (HR: 0.82 [0.59–1.16]). Conclusions: The independent influence of HPV-associated P16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor P16-status, indicating that the prognostic impact may be restricted to OPC only. 2014 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 113 (2014) 310–316 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

  • hpv associated P16 expression and response to hypoxic modification of radiotherapy in head and neck cancer
    Radiotherapy and Oncology, 2010
    Co-Authors: P Lassen, Jesper Grau Eriksen, Stephen Hamiltondutoit, Trine Tramm, Jan Alsner, Jens Overgaard
    Abstract:

    Abstract Background HPV/P16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using P16-status as a retrospective stratification parameter, we aimed to assess the influence of P16-expression on the response to nimorazole in HNSCC. Materials and methods Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for P16-expression. The influence of P16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5 years after radiotherapy. Results Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52–0.93]. Positive expression of P16 also significantly improved outcome after radiotherapy (0.41 [0.28–0.61]). In the subgroup of patients with P16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50–0.95]). However, in the P16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45–1.91]). Conclusions HPV/P16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/P16-negative tumours but was of no significant benefit in HPV/P16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours.

P Lassen - One of the best experts on this subject based on the ideXlab platform.

  • impact of hpv associated P16 expression on radiotherapy outcome in advanced oropharynx and non oropharynx cancer
    Radiotherapy and Oncology, 2014
    Co-Authors: P Lassen, Hanne Primdahl, Jorgen Johansen, Claus Kristensen, Elo Andersen, Lisbeth Juhler Andersen, Jan F Evensen, Jesper Grau Eriksen, Jens Overgaard
    Abstract:

    Background and purpose: HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/P16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPVassociated P16-expression in a cohort of patients with stage III–IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/ P16 also extends to tumors of non-oropharyngeal origin. Material and methods: 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by P16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. Results: Thirty-eight percent (490/1294) of the tumors were P16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p < .0001. In OPC P16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32–0.57]), event-free survival (EFS) (HR 0.44 [0.35–0.56]), and overall survival (OS) (HR: 0.38 [0.29–0.49]), respectively, compared with P16-negativity. In non-OPC no prognostic impact of P16-status was found for either endpoint: LRC (HR: 1.13 [0.75–1.70]), EFS (HR: 1.06 [0.76–1.47]), and OS (HR: 0.82 [0.59–1.16]). Conclusions: The independent influence of HPV-associated P16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor P16-status, indicating that the prognostic impact may be restricted to OPC only. 2014 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 113 (2014) 310–316 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

  • hpv associated P16 expression and response to hypoxic modification of radiotherapy in head and neck cancer
    Radiotherapy and Oncology, 2010
    Co-Authors: P Lassen, Jesper Grau Eriksen, Stephen Hamiltondutoit, Trine Tramm, Jan Alsner, Jens Overgaard
    Abstract:

    Abstract Background HPV/P16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using P16-status as a retrospective stratification parameter, we aimed to assess the influence of P16-expression on the response to nimorazole in HNSCC. Materials and methods Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for P16-expression. The influence of P16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5 years after radiotherapy. Results Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52–0.93]. Positive expression of P16 also significantly improved outcome after radiotherapy (0.41 [0.28–0.61]). In the subgroup of patients with P16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50–0.95]). However, in the P16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45–1.91]). Conclusions HPV/P16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/P16-negative tumours but was of no significant benefit in HPV/P16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours.

Anton Berns - One of the best experts on this subject based on the ideXlab platform.

  • p15 ink4b is a critical tumour suppressor in the absence of P16 ink4a
    Nature, 2007
    Co-Authors: Paul Krimpenfort, Annemieke Ijpenberg, Jiying Song, Martin Van Der Valk, Martijn C Nawijn, John Zevenhoven, Anton Berns
    Abstract:

    A locus on chromosome 9p21 which encodes three cell cycle inhibitors is frequently deleted in human cancer. Two of these, P16INKa and p14ARF, function as tumour suppressors. A new mouse model now shows that a third, p15INK4b, also contributes to the tumour suppressor function of this locus. Mice lacking all three show enhanced tumourigenesis and a broader tumour spectrum. The CDKN2b–CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15INK4b encoded by CDKN2b, P16INK4a encoded by CDKN2a and p14ARF (p19Arf in mice) encoded by an alternative reading frame of CDKN2a (ref. 1). Whereas the tumour suppressor functions for P16INK4a and p14ARF have been firmly established, the role of p15INK4b remains ambiguous. However, many 9p21 deletions also remove CDKN2b, so we hypothesized a synergistic effect of the combined deficiency for p15INK4b, p14ARF and P16INK4a. Here we report that mice deficient for all three open reading frames (Cdkn2ab-/-) are more tumour-prone and develop a wider spectrum of tumours than Cdkn2a mutant mice, with a preponderance of skin tumours and soft tissue sarcomas (for example, mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab-/- mouse embryonic fibroblasts (MEFs) are substantially more sensitive to oncogenic transformation than Cdkn2a mutant MEFs. Under conditions of stress, p15Ink4b protein levels are significantly elevated in MEFs deficient for P16Ink4a. Our data indicate that p15Ink4b can fulfil a critical backup function for P16Ink4a and provide an explanation for the frequent loss of the complete CDKN2b–CDKN2a locus in human tumours.

William H Liggett - One of the best experts on this subject based on the ideXlab platform.

  • role of the P16 tumor suppressor gene in cancer
    Journal of Clinical Oncology, 1998
    Co-Authors: William H Liggett, David Sidransky
    Abstract:

    Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor P16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of P16 in human cancer cell lines first suggested an important role for P16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that P16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of P16 gene alterations were observed in many primary tumors. In human neoplasms, P16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of P16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. P16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor...