DNA repair gene expression is increased in HPV positive head and neck squamous cell carcinomas

Holcomb, Andrew J.; Brown, Laura; Tawfik, Ossama; Madan, Rashna; Shnayder, Yelizaveta; Thomas, Sufi M.; Wallace, Nicholas A.

doi:10.1016/j.virol.2020.07.004

Cited by 7 publications

(6 citation statements)

References 45 publications

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“…In addition, given that fewer mutated DDR genes (such as in HPV-positive patients and in non-smokers) were found to be associated with improved survival, it is congruent with the HPV mutation results. This is in agreement with studies that have demonstrated increased expression (i.e., increased presence of functional copies) of DNA repair genes in HPV-positive HNSCC [30]. Two other studies reporting results from genomic cohorts originating from the University of Chicago and University of Michigan (120 and 34 patients, respectively) described that mutations in DDR genes and Fanconi Anemia genes (a spectrum that contains important overlapping genes), respectively, were more frequently associated with HPV positivity [27,31].…”

Section: Discussionsupporting

confidence: 93%

“…Existing literature suggests that expression of certain DDR genes, including BRCA1 and BRCA2, is associated with increased survival in HNSCC patients as the preservation of efficient repair mechanisms maintains genomic stability [32]. Similarly, another study has listed BRCA1 expression, alone, to be indicative of survival in HNSCC [30]. As another indicator of poor prognosis, patients with DDR gene mutations were significantly more likely to have more advanced disease burden at the time of the last visit, as measured in ctDNA and in both tDNA and/or ctDNA in the 6-gene and 3-gene subsets.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC

Burcher

Faucheux

Lantz

et al. 2021

Cancers

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PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC

Burcher

Faucheux

Lantz

et al. 2021

Cancers

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“…Therefore, DDR level represents the tumorigenesis and development process, as well as reflecting the efficacy of anti-tumor therapy to a certain extent. Considering the higher DNA repair gene/protein expression levels in HPV+ HNSCC tissue samples than those in HPV- HNSCC samples [ 13 ], the prognostic value and therapeutic efficacy value of DDR levels in HPV16- HNSCC patients need to be further clarified. In addition to the DDR level reflecting the malignant evolution of tumor cells, the tumor microenvironment (TM) around tumor cells also affects or reflects the malignant behavior of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients

Tang

2022

BMC Cancer

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Objectives To investigate prognostic-related gene signature based on DNA damage repair and tumor microenvironment statue in human papillomavirus 16 negative (HPV16-) head and neck squamous cell carcinoma (HNSCC). Methods For the RNA-sequence matrix in HPV16- HNSCC in the Cancer Genome Atlas (TCGA) cohort, the DNA damage response (DDR) and tumor microenvironment (TM) status of each patient sample was estimated by using the ssGSEA algorithm. Through bioinformatics analysis in DDR_high/TM_high (n = 311) and DDR_high/TM_low (n = 53) groups, a survival-related gene signature was selected in the TCGA cohort. Two independent external validation cohorts (GSE65858 (n = 210) and GSE41613 (n = 97)) with HPV16- HNSCC patients validated the gene signature. Correlations among the clinical-related hub differentially expressed genes (DEGs) and infiltrated immunocytes were explored with the TIMER2.0 server. Drug screening based on hub DEGs was performed using the CellMiner and GSCALite databases. The loss-of-function studies were used to evaluate the effect of screened survival-related gene on the motility of HPV- HNSCC cells in vitro. Results A high DDR level (P = 0.025) and low TM score (P = 0.012) were independent risk factors for HPV16- HNSCC. Downregulated expression of ALOX12B or SPRR1A was associated with poor survival rate and advanced cancer stages. The pathway enrichment analysis showed the DDR_high/TM_low samples were enriched in glycosphingolipid biosynthesis-lacto and neolacto series, glutathione metabolism, platinum drug resistance, and ferroptosis pathways, while the DDR_high/TM_low samples were enriched in Th17 cell differentiation, Neutrophil extracellular trap formation, PD − L1 expression and PD − 1 checkpoint pathway in cancer. Notably, the expression of ALOX12B and SPRR1A were negatively correlated with cancer-associated fibroblasts (CAFs) infiltration and CAFs downstream effectors. Sensitivity to specific chemotherapy regimens can be derived from gene expressions. In addition, ALOX12B and SPRR1A expression was associated with the mRNA expression of insulin like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), mammalian target of rapamycin (MTOR), and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) in HPV negative HNSCC. Down-regulation of ALOX12B promoted HPV- HNSCC cells migration and invasion in vitro. Conclusions ALOX12B and SPRR1A served as a gene signature for overall survival in HPV16- HNSCC patients, and correlated with the amount of infiltrated CAFs. The specific drug pattern was determined by the gene signature.

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“…DNA repair protein is correlated with HNSCC survival. The expression of DNA repair protein, especially the homologous recombination protein RAD51, is upregulated in HPV‐positive HNSCC (Holcomb et al., 2020). TREM‐1 expressed on myeloid cells correlates to HPV‐positive OPSCC progression (Azzimonti et al., 2021).…”

Section: Human Papillomavirusmentioning

confidence: 99%

Role of oral microbiome in oral oncogenesis, tumor progression, and metastasis

Gong

et al. 2022

Molecular Oral Microbiology

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Squamous cell carcinoma is the most common malignant tumor of the oral cavity and its adjacent sites, which endangers the physical and mental health of patients and has a complex etiology. Chronic infection is considered to be a risk factor in cancer development. Evidence suggests that periodontal pathogens, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, are associated with oral squamous cell carcinoma (OSCC). They can stimulate tumorigenesis by promoting epithelial cells proliferation while inhibiting apoptosis and regulating the inflammatory microenvironment. Candida albicans promotes OSCC progression and metastasis through multiple mechanisms. Moreover, oral human papillomavirus (HPV) can induce oropharyngeal squamous cell carcinoma (OPSCC). There is evidence that HPV16 can integrate with host cells' DNA and activate oncogenes. Additionally, oral dysbiosis and synergistic effects in the oral microbial communities can promote cancer development. In this review, we will discuss the biological characteristics of oral microbiome associated with OSCC and OPSCC and then highlight the mechanisms by which oral microbiome is involved in oral oncogenesis, tumor progression, and metastasis. These findings may have positive implications for early diagnosis and treatment of oral cancer.

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DNA repair gene expression is increased in HPV positive head and neck squamous cell carcinomas

Cited by 7 publications

References 45 publications

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC

Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients

Role of oral microbiome in oral oncogenesis, tumor progression, and metastasis

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