HPV transcript expression affects cervical cancer response to chemoradiation

Abstract

Persistent HPV infection is causative for the majority of cervical cancer (CC) cases; however, current guidelines do not require HPV testing for newly diagnosed CC. Using an institutional cohort of 88 CC patients treated uniformly with standard-of-care chemoradiation (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared to patients with HPV 16 positive tumors, consistent with previously published studies.Using RNAseq analysis we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n=304). For the first time transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional dataset (n=88), and within the HPV 16 positive subset (n=36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct p53-p21 dependent mechanisms. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy and these patients may benefit from alternative treatment strategies.

HPV-Positive and -Negative Cervical Cancers Are Immunologically Distinct

“…As HPV-positive CC is commonly caused by several distinct HPV species, we also compared the tumor immune microenvironments between CC associated with HPV α9 (HPV16-like) and HPV α7 (HPV18-like), the most common HPV species involved in CC. These distinct HPV species exhibit a number of molecular differences [ 17 ] and have been associated with different patient outcomes [ 10 , 14 , 15 , 16 ]. Notably, immunological differences between HPV α9 and HPV α7 have also not been systematically characterized.…”

“…Patients with HPV-positive CC appear to have a more favorable prognosis than their HPV-negative counterparts [ 8 , 9 , 10 , 11 ], and it is clear that HPV-positive and HPV-negative diseases are clinically and pathologically distinct [ 12 , 13 ]. Although somewhat controversial, patient outcomes for HPV16-positive CC appear superior to those that are HPV18-positive [ 10 , 14 , 15 , 16 ]. From a tumor virus perspective, these results may not be surprising, given the divergence in sequence and molecular function between the oncogenes encoded by the different HPV types [ 17 ].…”

Improving cervical cancer survival–A multifaceted strategy to sustain progress for this global problem

“…Work is ongoing to determine how additional biologic differences, such as HPV alternative transcript expression, may influence CRT and DNA damage response inhibitor sensitivity. 85 Recent work has also highlighted the potential for other aspects of the tumor microbiome in addition to HPV, such as bacterial and fungal species, to influence tumor responses to CRT. [86][87][88][89] Much of this developing work highlights the connection between the microbiome and the tumor immune microenvironment, which may support the potential for radiation to successfully induce systemic antitumor immune responses.…”

“…Sensitivity to this class of drugs, however, is not uniform among HPV‐positive cervical tumors, even within the same HPV genotype. Work is ongoing to determine how additional biologic differences, such as HPV alternative transcript expression, may influence CRT and DNA damage response inhibitor sensitivity 85 . Recent work has also highlighted the potential for other aspects of the tumor microbiome in addition to HPV, such as bacterial and fungal species, to influence tumor responses to CRT 86–89 .…”

MicroRNA‐506 ameliorates breast cancer‐induced osteolytic bone metastasis via the NFATc‐1 signaling pathway

“…Previous studies have reported different strategies that are used to treat cancers including breast cancer, such as the enhanced efficacy of doxorubicin in solid tumor cells by methylβ-cyclodextrin, [17] the inhibition of breast cancer growth in preclinical model by inducing autophagic cell death with bitter melon extract, [18] and also in cervical carcinomas. [19][20][21][22] Here, we constructed a breast cancer-induced osteolytic bone metastasis model to explore the potential role of miR-506 and the underlying molecular mechanisms. We found that miR-506 was downregulated in breast cancer.…”