Activation of DNA damage repair factors in HPV positive oropharyngeal cancers.
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ABSTRACT:
SUBMITTER: Kono T
PROVIDER: S-EPMC7333731 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Activation of DNA damage repair factors in HPV positive oropharyngeal cancers.
Kono Takeyuki T Hoover Paul P Poropatich Kate K Paunesku Tatjana T Mittal Bharat B BB Samant Sandeep S Laimins Laimonis A LA
Virology 20200522
The mechanisms regulating viral pathogenesis of human papillomavirus (HPV) associated oropharyngeal squamous cell cancers (OPSCC) are not well understood. In the cervix, activation of DNA damage repair pathways is critical for viral replication but little is known about their role in OPSCC. APOBEC factors have been shown to be increased in OPSCC but the significance of this is unclear. We therefore examined activation of DNA damage and APOBEC factors in HPV-induced OPSCC. Our studies show signif ...[more]
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Project description:The role of human papillomavirus (HPV) status for the prognosis of oropharyngeal cancers (OPCs) is discussed controversially. Here, we present an analysis of 144,969 head and neck cancer cases (ICD-10 codes: C00-C13) with a sub-cohort of 62,775 tumor cases of the oropharynx (C01, C09, and C10). To this end, de-identified data from electronic health records of about 60 healthcare organizations from 30 different countries were used. Odds ratios, hazard ratios (HRs), and Kaplan-Meier analyses were used to compare outcomes between different cancer entities of neoplasms of the base of the tongue (C01), of tonsils (C09), and of the oropharynx (C10) of women and men with and without HPV infection. To avoid the bias from different age distributions, the cohorts were balanced using propensity score matching. The 5-year survival rate for HPV-positive patients is somewhat better than that for HPV-negative patients, but for age- and sex-balanced cohorts, there remains no significant advantage for HPV-positive patients [HR, 1.126 (0.897-1.413)]. Looking at the different entities and HPV status for age-matched male and female patients separately, HPV is a significantly positive prognostic factor for female patients in some entities, whereas for male patients, it is only a positive prognostic factor for malignant neoplasms of oropharynx (C10) [HR, 1.077 (0.602-1.926)].
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Project description:ImportanceCirculating tumor tissue-modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide pretreatment interpatient variability are not well understood.ObjectiveTo characterize clinicopathologic factors associated with TTMV HPV DNA.Design, setting, and participantsThis cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment.ExposuresClinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings.Main outcomes and measuresPretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction-based assay, considered as either detectable/undetectable or a continuous score (fragments/mL).ResultsAmong 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60 061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 [88%]), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 [58%]) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 [100%] vs 9 of 15 [60%]).Conclusions and relevanceIn this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.
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Project description:BackgroundThe revised 8th Edition American Joint Committee on Cancer (AJCC) Head and Neck Staging Manual distinguishes HPV-mediated from non-HPV-mediated oropharyngeal cancer (OpSCC). The objective was to analyze OpSCC treatment modalities and outcomes.MethodsA retrospective study of OpSCC patients treated with radiotherapy or chemoradiotherapy between January 1st, 2000, and December 31st, 2008, as identified from the BC Cancer Registry. All patients received treatment at cancer clinics and had at least 5 years follow-up post-treatment. A total of 1259 OpSCC patients were identified. After initial chart reviews, 288 patients were excluded from further analysis and the majority (n = 198) was due to not receiving curative treatment. Based on the availability of formalin-fixed, paraffin-embedded (FFPE) tissue, patients were divided into two cohorts: Study Cohort (FFPE available, n = 244) and General Cohort (FFPE unavailable, n = 727). The Study Cohort was restaged according to AJCC 8th Edition based on p16 immunohistochemistry status. Kaplan-Meier analysis was used to estimate the 5-year overall survival (OS), disease-specific survival (DSS), and locoregional recurrence-free survival (LFS).ResultsAmong 971 patients, OpSCC age-adjusted incidence rate was observed to have increased from 2.1 to 3.5 per 100,000 between 2000 and 2008. The General Cohort was relatively older than the Study Cohort (60.1 ± 10.5 vs. 57.3 ± 9.4), but both cohorts were predominantly males (78.3% vs. 76.2%). Amongst the Study Cohort, 77.5% were p16-positive, of whom 98.4% were down staged in the 8th Edition. These early-stage patients showed OS improvement for those treated with chemoradiation, compared to radiation alone (85.8% vs. 73.1%, p = 0.05).ConclusionsOpSCC incidence is increasing in BC. The addition of chemotherapy to radiotherapy may portend a benefit in OS even for early-stage p16-positive OpSCC. Additional research is necessary to assess the safety of treatment de-escalation even among early-stage disease.
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Project description:Opinion statementHuman papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.
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Project description:Background and purposeHuman papillomavirus-positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV-positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics.Materials and methodsA retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV-negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar χ(2) test was used for the matched-pair analysis.ResultsBy imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV-negative primary tumors were more likely to be isoattenuated and demonstrate ill-defined borders, though these results were not statistically significant. HPV-positive tumors were more likely to demonstrate cystic nodal metastases than HPV-negative tumors (36% versus 9%, P = .002).ConclusionsIn this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle.
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Project description:Squamous cell carcinoma of the head and neck (HNSCC) consist of two distinct biological entities. While the numbers of classical, tobacco-induced HNSCC are declining, tumors caused by human papillomavirus (HPV) infection are increasing in many countries. HPV-positive HNSCC mostly arise in the oropharynx and are characterized by an enhanced sensitivity towards radiotherapy and a favorable prognosis. To identify molecular differences between both entities on the protein level, we conducted a mass spectrometric comparison of eight HPV-positive and nine HPV-negative oropharyngeal tumors (OPSCC). Overall, we identified 2051 proteins, of which 31 were found to be differentially expressed. Seventeen of these can be assorted to three functional groups, namely DNA replication, nuclear architecture and cytoskeleton regulation, with the differences in the last group potentially reflecting an enhanced migratory and invasive capacity. Furthermore, a number of identified proteins have been described to directly impact on DNA double-strand break repair or radiation sensitivity (e.g., SLC3A2, cortactin, RBBP4, Numa1), offering explanations for the differential prognosis. The unequal expression of three proteins (SLC3A2, MCM2 and lamin B1) was confirmed by immunohistochemical staining using a tissue microarray containing 205 OPSCC samples. The expression levels of SLC3A2 and lamin B1 were found be of prognostic relevance in patients with HPV-positive and HPV-negative OPSCC, respectively.
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Project description:Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.
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Project description:The treatment of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) continues to evolve as multiple ongoing and recently completed clinical trials investigate the role of surgery, radiation therapy, chemotherapy, and immunotherapy. Current trials are investigating transoral robotic surgery (TORS) in treatment de-escalation protocols in an effort to optimize quality of life, while maintaining historical survival rates. The advantage of TORS is its minimally invasive approach to primary resection of the tumor as well as valuable pathologic staging. The ORATOR trial reported poorer quality of life in patients treated with TORS compared to primary radiotherapy though this was not a clinically meaningful difference. The recently published ECOG 3311 trial showed that surgery can be used to safely de-escalate the adjuvant radiation dose to 50 Gy in intermediate-risk patients. In this review, we summarize and discuss the past and current clinical trials involving surgery in the treatment of HPV-positive OPSCC.
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