Specific Deletion of p16 with Retention of p19 Enhances the Development of Invasive Oral Squamous Cell Carcinoma

Ishida, Kazuhisa; Tomita, Hiroyuki; Kanayama, Tomohiro; Noguchi, Kei; Niwa, Ayumi; Kawaguchi, Masaya; Miyai, Masafumi; Matsuo, Mikiko; Imaizumi, Yuko; Kato, Kazúo; Hatano, Yuichiro; Hirata, Akihiro; Okada, Hideshi; Shibata, Toshiyuki; Hara, Akira

doi:10.1016/j.ajpath.2020.01.017

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…Recently, immunogenic analysis of clinical specimens from TCGA study and immune checkpoint trials across various cancer types and demonstrates 9p21 loss as a ubiquitous genomic correlate of the “cold” tumor-immune phenotype and primary resistance to immune checkpoint therapy ( 106 , 107 ). Recently, Cdkn2a null mice exposed with 4NQO developed faster and more pronounced oral lesions compared to control mice; and proliferation of tumor cells with Cdkn2a gene deletion was associated with the progression of OSCC in mice ( 108 ). More studies are necessary in this mouse models to confirm the role of Cdkn2a in the immune surveillance mechanism of OPLs.…”

Section: Regulation Of the Immune Microenvironment By Genomic Changes...mentioning

confidence: 99%

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

et al. 2022

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Oral premalignant lesions (OPLs) are the precursors to oral cavity cancers, and have variable rates of progression to invasive disease. As an intermediate state, OPLs have acquired a subset of the genomic alterations while arising in an oral inflammatory environment. These specific genomic changes may facilitate the transition to an immune microenvironment that permits malignant transformation. Here, we will discuss mechanisms by which OPLs develop an immunosuppressive microenvironment that facilitates progression to invasive cancer. We will describe how genomic alterations and immune microenvironmental changes co-evolve and cooperate to promote OSCC progression. Finally, we will describe how these immune microenvironmental changes provide specific and unique evolutionary vulnerabilities for targeted therapies. Therefore, understanding the genomic changes that drive immunosuppressive microenvironments may eventually translate into novel biomarker and/or therapeutic approaches to limit the progression of OPLs to potential lethal oral cancers.

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Section: Regulation Of the Immune Microenvironment By Genomic Changes...mentioning

confidence: 99%

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

et al. 2022

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“…Inactivation of the p16 INK4a gene is prevalent in head-neck and oral SCCs and this inactivation is believed to be brought about by a variety of mechanisms including homozygous deletion, DNA methylation, and point mutation. [28][29][30][31] Various ideas exist regarding the immunohistochemical evaluation of p16 INK4a gene inactivation. Sanchez-Cespedes et al argue that immunohistochemical loss of p16 INK4a is connected to the inactivation of the p16 INK4a gene.…”

Section: Resultsmentioning

confidence: 99%

p16 INK4a , and p14 ARF Expressions in Carcinogenesis of Squamous Cell Carcinoma of the Lip

Akatlı¹,

Ayva²,

Bozdoğan³

2022

Clin Cancer Investig J

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The goal of this study was to clarify the role of p16 INK4a , p14 ARF, and p53 protein expressions in carcinogenesis in squamous cell carcinomas of the lip. The expressions of the p53, p16 INK4a , and p14 ARF proteins were examined in 46 formaline-fixed paraffin embedded tissue specimens, which included 19 cases of squamous cell carcinoma of the lip, 14 cases of actinic cheilitis, and 13 cases of normal mucosa. Immunoreactivity in the peritumoral epithelium adjacent to squamous cell carcinomas was also evaluated. p16 INK4a expression was increased in actinic cheilitis in comparison with normal mucosa (p=0.001). p14 ARF expression progressively increased from normal mucosa to actinic cheilitis (p=0.001) and was observed to decrease significantly during the process of transition from actinic cheilitis to carcinoma (p=0.003). p53 values progressively increased from normal mucosa to actinic cheilitis (p=0.001) and carcinoma (p=0.008). A significant positive correlation was found between p14 ARF and p53 in the peritumoral epithelium adjacent to carcinomas. Our findings indicated that p16 INK4a and p14 ARF immunohistochemistry does not determine whether or not actinic cheilitis has the potential to develop carcinoma. The p14 ARF /p53 pathway is activated in the peritumoral epithelium adjacent to carcinoma; however, this activation would not be adequate to prevent carcinogenesis.

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“… 33 Several independent studies demonstrated that loss‐of‐function CDKN2A in oral cancer is correlated with worsened prognoses. 34 , 35 , 36 Interestingly, data from a mouse model with cdkn2a −/− genotype showed that cdkn2a loss of function is a rate‐limiting step in oral cancer formation 37 and targeting the CDK4/CDKN1A/RB1 pathway may be an attractive strategy to treat OSCC. 38 CYLD also can regulate cell‐cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.…”

Section: Discussionmentioning

confidence: 99%

Comparison of mutation landscapes of pretreatment versus recurrent squamous cell carcinoma of the oral cavity: The possible mechanism of resistance to standard treatment

Payungwong,

Angkulkrerkkrai,

Chaiboonchoe

et al. 2024

Cancer Reports

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BackgroundA high recurrent rate of oral squamous cell carcinoma (OSCC) is a major concern in head and neck cancer treatment. The study of the genetic mutation landscape in recurrent OSCC may provide information on certain mutations associated with the pathobiology and treatment response of the OSCC.AimWe investigated the mutation landscape of matched pretreatment and recurrent tumors to understand the influence of genetic mutations on the pathobiology and clinical outcomes in OSCC.Methods and ResultsWe sequenced 33 formalin‐fixed paraffin‐embedded (FFPE) recurrent tumors, primary tumors, and primary tumors before recurrence that matched the recurrent tumors collected from Rajavithi Hospital during 2019–2021. We identified recurrent mutations from these samples by the Oncomine Ion Torrent‐based next‐generation sequencing on the 517 cancer‐associated gene panel. From the results, we found that the most commonly mutated gene in the cohort is a histone methyltransferase KMT2D (54.55%), implicating that aberrance in epigenetic regulation may play a role in oral cancer tumorigenesis. Functional protein association network analysis of the gene frequently mutated in the recurrent tumors showed enrichment of genes that regulate the cancer cell cycle, that is, MRE11A, CDKN2A, and CYLD. This finding was confirmed in the primary‐recurring matched pair. We found that recurrent tumors possess a small but recurring group of genes, with presumably the subclonal mutations driving the recurrence of the tumor, suggesting that the recurrent disease originated from a small fraction of the cancer cell that survives standard treatment. These genes were absent in the primary tumor with a good response to the standard treatment. On the other hand, we found an enrichment of DNA repair genes, namely ATR, BRCA1, BRCA2, RAD50, and MUTYH, in nonrecurrent tumors suggesting that the mutations in the DNA repair pathway may at least partially explain the different response to the standard treatment.ConclusionsOur pilot study identified pathways of carcinogenesis in oral cancer and specific gene sets that indicate treatment responses and prognoses in this group of patients.

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Specific Deletion of p16 with Retention of p19 Enhances the Development of Invasive Oral Squamous Cell Carcinoma

Cited by 12 publications

References 32 publications

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

p16 INK4a , and p14 ARF Expressions in Carcinogenesis of Squamous Cell Carcinoma of the Lip

Comparison of mutation landscapes of pretreatment versus recurrent squamous cell carcinoma of the oral cavity: The possible mechanism of resistance to standard treatment

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