HPV16 RNA patterns defined by novel high-throughput RT-qPCR as triage marker in HPV-based cervical cancer precursor screening

Höfler, Daniela; Böhmer, Gerd; Wasielewski, Reinhard von; Neumann, Heinrich; Halec, Gordana; Holzinger, Dana; Dondog, Bolormaa; Gissmann, Lutz; Pawlita, Michael; Schmitt, Markus

doi:10.1016/j.ygyno.2015.06.039

Cited by 8 publications

(13 citation statements)

References 34 publications

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“…Several studies showed that HPV gene expression pattern could be useful as viral molecular marker of tumor progression [48–50]. Analysis of E6 and E7 mRNA levels, together with other clinical data, seems useful to assess the risk of progression of cervical SCC and oropharyngeal SCC cases [43, 51, 52].…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma

et al. 2017

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Human papillomavirus type 16 (HPV16) is the major cause of cervical cancer and of a fraction of oropharyngeal carcinoma. Few studies compared the viral expression profiles in the two types of tumor. We analyzed HPV genotypes and viral load as well as early (E2/E4, E5, E6, E6*I, E6*II, E7) and late (L1 and L2) gene expression of HPV16 in cervical and oropharyngeal cancer biopsies. The study included 28 cervical squamous cell carcinoma (SCC) and ten oropharyngeal SCC, along with pair-matched non-tumor tissues, as well as four oropharynx dysplastic tissues and 112 cervical intraepithelial neoplasia biopsies. Viral load was found higher in cervical SCC (<1 to 694 copies/cell) and CIN (<1 to 43 copies/cell) compared to oropharyngeal SCC (<1 to 4 copies/cell). HPV16 E2/E4 and E5 as well as L1 and L2 mRNA levels were low in cervical SCC and CIN and undetectable in oropharynx cases. The HPV16 E6 and E7 mRNAs were consistently high in cervical SCC and low in oropharyngeal SCC. The analysis of HPV16 E6 mRNA expression pattern showed statistically significant higher levels of E6*I versus E6*II isoform in cervical SCC (p = 0.002) and a slightly higher expression of E6*I versus E6*II in oropharyngeal cases. In conclusion, the HPV16 E5, E6, E6*I, E6*II and E7 mRNA levels were more abundant in cervical SCC compared to oropharyngeal SCC suggesting different carcinogenic mechanisms in the two types of HPV-related cancers.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma

et al. 2017

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“…Transcript ratios were calculated for E6*II or E6*I over E1 ∧ E4, and for E1C over L1. The cutoffs for viral RNA patterns positivity in both assays were previously defined on HPV DNA‐positive cervical cell samples . Presence of viral RNA patterns has been demonstrated to be the best molecular marker among HPV DNA, viral load and p16 INK4a to define HPV‐driven OPSCC and to predict best improved survival.…”

Section: Methodsmentioning

confidence: 99%

Sensitivity and specificity of antibodies against HPV16 E6 and other early proteins for the detection of HPV16‐driven oropharyngeal squamous cell carcinoma

Holzinger

Wichmann

Baboci

et al. 2017

Intl Journal of Cancer

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103

115

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To determine the sensitivity and specificity of HPV16 serology as diagnostic marker for HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), 214 HNSCC patients from Germany and Italy with fresh-frozen tumor tissues and sera collected before treatment were included in this study. Hundred and twenty cancer cases were from the oropharynx and 94 were from head and neck cancer regions outside the oropharynx (45 oral cavity, 12 hypopharynx and 35 larynx). Serum antibodies to early (E1, E2, E6 and E7) and late (L1) HPV16 proteins were analyzed by multiplex serology and were compared to tumor HPV RNA status as the gold standard. A tumor was defined as HPV-driven in the presence of HPV16 DNA and HPV16 transformation-specific RNA transcript patterns (E6*I, E1 E4 and E1C). Of 120 OPSCC, 66 (55%) were HPV16-driven. HPV16 E6 seropositivity was the best predictor of HPV16-driven OPSCC (diagnostic accuracy 97% [95%CI 92-99%], Cohen's kappa 0.93 [95%CI 0.8-1.0]). Of the 66 HPV-driven OPSCC, 63 were HPV16 E6 seropositive, compared to only one (1.8%) among the 54 non-HPV-driven OPSCC, resulting in a sensitivity of 96% (95%CI 88-98) and a specificity of 98% (95%CI 90-100). Of 94 HNSCC outside the oropharynx, six (6%) were HPV16-driven. In these patients, HPV16 E6 seropositivity had lower sensitivity (50%, 95%CI 19-81), but was highly specific (100%, 95%CI 96-100). In conclusion, HPV16 E6 seropositivity appears to be a highly reliable diagnostic marker for HPV16-driven OPSCC with very high sensitivity and specificity, but might be less sensitive for HPV16-driven HNSCC outside the oropharynx.

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“…In women, cervical cancer is the third most commonly diagnosed malignant tumor of the reproductive tract worldwide, accounting for an estimated 274,000 deaths worldwide annually [ 1 ]. Numerous studies have indicated that high risk TYPES of human papillomavirus (HPV) infection is a main risk for cervical development, but it remains unsatisfactory in diagnosis and predicting prognosis [ 2 ]. Advances in therapeutic methods and diagnostic tools have decreased the incidence and mortality of cervical cancer [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

B3GNT3 Expression Is a Novel Marker Correlated with Pelvic Lymph Node Metastasis and Poor Clinical Outcome in Early-Stage Cervical Cancer

et al. 2015

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BackgroundThe β1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) encodes a member of the B3GNT family that functions as the backbone structure of dimeric sialyl-Lewis A and is involved in L-selectin ligand biosynthesis, lymphocyte homing and lymphocyte trafficking. B3GNT3 has been implicated as an important element in the development of certain cancers. However, the characteristics of B3GNT3 in the development and progression of cancer remain largely unknown. Thus, our study aimed to investigate the expression pattern and the prognostic value of B3GNT3 in patients with early-stage cervical cancer.MethodsThe mRNA and protein levels of B3GNT3 expression were examined in eight cervical cancer cell lines and ten paired cervical cancer tumors, using real-time PCR and western blotting, respectively. Immunohistochemistry (IHC) was used to analyze B3GNT3 protein expression in paraffin-embedded tissues from 196 early-stage cervical cancer patients. Statistical analyses were applied to evaluate the association between B3GNT3 expression scores and clinical parameters, as well as patient survival.Results B3GNT3 expression was significantly upregulated in cervical cancer cell lines and lesions compared with normal cells and adjacent noncancerous cervical tissues. In the 196 cases of tested early-stage cervical cancer samples, the B3GNT3 protein level was positively correlated with high risk TYPES of human papillomavirus (HPV) infection (P = 0.026), FIGO stage (P < 0.001), tumor size (P = 0.025), tumor recurrence (P = 0.004), vital status (P < 0.001), concurrent chemotherapy and radiotherapy (P = 0.016), lymphovascular space involvement (P = 0.003) and most importantly, lymph node metastasis (P = 0.003). Patients with high B3GNT3 expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with those with low expression of this protein. Multivariate analysis suggested that B3GNT3 expression is an independent prognostic indicator for cervical cancer patients.ConclusionsOur study demonstrated that elevated B3GNT3 expression is associated with pelvic lymph node metastasis and poor outcome in early-stage cervical cancer patients. B3GNT3 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.

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HPV16 RNA patterns defined by novel high-throughput RT-qPCR as triage marker in HPV-based cervical cancer precursor screening

Cited by 8 publications

References 34 publications

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma

Sensitivity and specificity of antibodies against HPV16 E6 and other early proteins for the detection of HPV16‐driven oropharyngeal squamous cell carcinoma

B3GNT3 Expression Is a Novel Marker Correlated with Pelvic Lymph Node Metastasis and Poor Clinical Outcome in Early-Stage Cervical Cancer

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