Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma

Carvalho, Ana Carolina de; Pérdomo, Sandra; Santos, Wellington dos; Fernandes, Gabriela; Jesus, Lais Machado de; Carvalho, Raiany Santos; Scapulatempo‐Neto, Cristovam; Almeida, Gisele Caravina de; Sorroche, Bruna Pereira; Arantes, Lídia Maria Rebolho Batista; Melendez, Matias Eliseo; Marchi, Pedro De; Hayes, Nancy S.; Reis, Rui Manuel

doi:10.1038/s41598-020-66741-z

Cited by 7 publications

(3 citation statements)

References 70 publications

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“…A recent study of de Carvalho et al has shown that HPV-negative OPSCC tumors usually have a high mutation burden respect to HPV-positive ones [ 41 ]. In particular, TP53 mutations are frequently found in OPSCC driven by alcohol and tobacco, whereas their presence has been reported in only a small subset of HPV-related OPSCC so far [ 42 – 46 ].…”

Section: Discussionmentioning

confidence: 99%

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

et al. 2022

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Background and purpose Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. Results In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival—OS: 28.1% for LINE-1 methylation < 35% vs. 69.1% for ≥ 55%; p < 0.0001). When LINE-1 methylation was dichotomized as < 55% versus ≥ 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24–10.38) and progression (HR 4.54, 95% CI 2.18–9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 ≥ 50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53 ≥ 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine–phosphate–guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. Conclusions Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.

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Section: Discussionmentioning

confidence: 99%

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

et al. 2022

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“…There have been studies conducted to elicit whether particular somatic mutations are identified in this cohort of patients, in an attempt to correlate which patients are associated with a worse overall outcome. NOTCH1 and PTEN mutations were linked with a reduced recurrence free survival in patients with HPV positive OPSCC ( de Carvalho et al, 2020 ), with PIK3CA mutations linked with reduced disease free survival in those on de-intensified CRT ( Beaty et al, 2019 ). Conversely, FGFR3 mutations in HPV positive OPSCC are linked with improved disease free survival ( BERSANI et al, 2018 ).…”

Section: Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma Linked With Disease Progression/recurrencementioning

confidence: 99%

The Role of Human Papilloma Virus in Dictating Outcomes in Head and Neck Squamous Cell Carcinoma

Brennan

Baird

O’Regan

et al. 2021

Front. Mol. Biosci.

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The Human Papilloma Virus (HPV) is an oncogenic virus which is associated with the development of head and neck squamous cell carcinoma (HNSCC), predominantly within the oropharynx. Approximately 25% of oropharyngeal squamous cell carcinoma (OPSCC) cases worldwide are attributable to HPV infection, with an estimated 65% in the United States. Transmission is via exposure during sexual contact, with distinctive anatomical features of the tonsils providing this organ with a predilection for infection by HPV. No premalignant lesion is identifiable on clinical examination, thus no comparative histological features to denote the stages of carcinogenesis for HPV driven HNSCC are identifiable. This is in contrast to HPV-driven cervical carcinoma, making screening a challenge for the head and neck region. However, HPV proffers a favorable prognosis in the head and neck region, with better overall survival rates in contrast to its HPV negative counterparts. This has resulted in extensive research into de-intensifying therapies aiming to minimize the morbidity induced by standard concurrent chemo-radiotherapy without compromising efficacy. Despite the favorable prognosis, cases of recurrence and/or metastasis of HPV positive HNSCC do occur, and are linked with poor outcomes. HPV 16 is the most frequent genotype identified in HNSCC, yet there is limited research to date studying the impact of other HPV genotype with respect to overall survival. A similar situation pertains to genetic aberrations associated in those with HPV positive HNSCC who recur, with only four published studies to date. Somatic mutations in TSC2, BRIP1, NBN, TACC3, NFE2l2, STK11, HRAS, PIK3R1, TP63, and FAT1 have been identified in recurrent HPV positive OPSCC. Finding alternative therapeutic strategies for this young cohort may depend on upfront identification of HPV genotypes and mutations which are linked with worse outcomes, thus ensuring appropriate stratification of treatment regimens.

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“…However, infection with the Human Papilloma Virus (HPV) high-risk types are increasingly detected and currently considered one oncogenic driver in a subset of cases [ 2 ]. HNSCCs also harbor a high genetic heterogeneity, with mutations in tumor suppressor genes such as TP53 and p16INK4a and activation of oncogenes, such as the epidermal growth factor receptor ( EGFR ) and PIK3CA [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines

Gomes

Oliveira

Silva

et al. 2022

Cells

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Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC50 compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.

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Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma

Cited by 7 publications

References 70 publications

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

The Role of Human Papilloma Virus in Dictating Outcomes in Head and Neck Squamous Cell Carcinoma

Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines

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