Prevalence of high-risk human papillomavirus infection and cancer gene mutations in nonmalignant tonsils

Ilmarinen, Taru; Munne, Pauliina; Hagström, Jaana; Haglund, Caj; Auvinen, Eeva; Virtanen, Elina; Haesevoets, Annick; Speel, Ernst J. M.; Aaltonen, Leena-Maija

doi:10.1016/j.oraloncology.2017.08.010

Cited by 14 publications

(18 citation statements)

References 40 publications

(52 reference statements)

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“…The latter finding is consistent with early loss of heterozygosity (LOH) on Chr 11q and 17q in premalignant lesions of the oral cavity (Califano et al 1996). A recent observation that mutations in PIK3CA, EP300, NF1, or RB1 co-occurred with high-risk HPV infections in benign tonsil specimens suggested that they could serve as potential biomarkers for risk of progression (Ilmarinen et al 2017). We anticipate that these data will inform potential secondary prevention strategies for HPV-positive OSCCs among individuals with oral high-risk HPV infections, via genomic profiling of oral rinse or circulating cell-free DNA specimens.…”

Section: Discussionsupporting

confidence: 63%

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

et al. 2018

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Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5 ′-ATN-3 ′ correlated with tobacco exposure. Universal expression of HPV E6 * 1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D,

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Section: Discussionsupporting

confidence: 63%

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

et al. 2018

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“…Regarding the important role of HPV in OPSCC, several studies have investigated the presence of HPV infection in the non-malignant tonsil tissues of cancer-free individuals or in adjacent tumors ( 8 – 11 ) as well as in the genomic profiles of premalignant lesions prior to oral cancer ( 15 ). Attempts to detect HPV infection in almost 4,000 non-tumor tonsil tissue specimens in the UK did not find evidence of an association with HPV ( 10 ), and two other studies conducted in Finland and in the US found that only 1.0% and 3.1% of patients, respectively, had high-risk HPV infections (in 477 and 5,579 non-malignant tonsil tissues, respectively) ( 9 , 11 ). Nevertheless, in-depth genomic characterization of the normal to premalignant to malignant transition process driven by persistent HPV16 infection in OPSCC has not been performed.…”

Section: Discussionmentioning

confidence: 96%

“…However, intensive efforts to detect active HPV16 in tissues surrounding such tumors have provided scant evidence of this process ( 8 ). In addition, studies examining the prevalence of HPV infection in non-tumor tonsillar specimens have been performed ( 9 – 11 ) but have failed to find or have found only a low (1%-3.1%) rate of high-risk HPV infection. Thus, HPV-infected non-tumor tissues are rare; and no comparative analyses of HPV-infected non-tumor and corresponding tumor tissues, which might elucidate the precise serial action of HPV, have yet been reported.…”

Section: Introductionmentioning

confidence: 99%

Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16

et al. 2018

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Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of 94.3× for WES and 35.3× for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.

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“…According to PCR, 2 of the 195 (1.0%) DNA samples isolated from the tonsil tissue were positive for HPV-16 in a German group study [ 30 ]. At the Helsinki University Hospital, 13 of the 206 (6.3%) samples were positive for HPV DNA in a 2001 to 2003 study and 5 of the 477 (1.0%) patients were detected positive for HPV DNA in a 2012 and 2015 study [ 31 , 32 ]. The observation that oral rinse test is less sensitive in the detection of HPV-associated tonsil cancers highlights its limitation as a screening tool.…”

Section: Discussionmentioning

confidence: 99%

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer

et al. 2020

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Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan–Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.

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Prevalence of high-risk human papillomavirus infection and cancer gene mutations in nonmalignant tonsils

Abstract: The prevalence of high-risk HPV in nonmalignant tonsils is low. High-risk HPV positive tonsils harbored mutations in genes that are commonly altered in HPV-associated head and neck SCC. The role of these mutations in tonsillar carcinogenesis is an interesting target for future research.

Cited by 14 publications

References 40 publications

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer

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