Current and Emerging Molecular Tests for Human Papillomavirus–Related Neoplasia in the Genomic Era

Abstract

Laboratory tests have a key role in preventing human papillomavirus (HPV)-driven carcinomas and in guiding therapeutic interventions. An understanding of the virology, immunology, and carcinogenesis of HPV is essential for choosing appropriate diagnostic test modalities and developing new and even more effective cancer prevention strategies. HPV infects basal epithelial cells on multiple surfaces and induces carcinoma primarily in the cervix and the oropharynx. HPV types are stratified as high risk or low risk based on their carcinogenic potential. During oncogenesis, HPV interferes with cell cycle regulation and incites DNA damage responses that thwart apoptosis and enable mutations to accumulate. Such mutations are an adverse effect of innate and adaptive antiviral immune responses that up-regulate DNA-editing enzymes, with natural selection of cells having a chromosomally integrated viral genome lacking expression of viral proteins targeted by the immune system. Infected cancers share a similar mutation signature, reflecting the effect of apolipoprotein B mRNA-editing catalytic polypeptide enzyme DNA-editing enzymes. It is feasible that genomic tests for characteristic mutations or methylation signatures, along with tests for dysregulated HPV gene expression, add value in predicting behavior of premalignant lesions. Furthermore, these tumor markers in cell-free DNA of plasma or body fluids may one day assist in early detection or monitoring cancer burden during treatment.

Inclusion of an E7 DNA Amplification Test Improves the Robustness of Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma Diagnosis

“…HPV E7 was selected as the PCR target because of its role as the most potent HPV oncogene that is integrated, whereas E5 is lost during genomic integration [32]. Although several Food and Drug Administration (FDA)approved commercial tests are available for detecting highrisk HPV in cervical specimens, currently no FDA-approved tests are available for detecting high-risk HPV in OPSCC [33]. While the detection of HPV E7 RNA would be more indicative of a persistent infection associated with a carcinoma rather than a transient infection, a DNA test was developed instead of an RNA test due to the unreliability of extracting high quality RNA from FFPE tissues.…”

“…behavior patterns [12]. While more than 200 HPV types are known, only 13 to 15 high-risk HPV types are oncogenic, with HPV16 causing more than 90% of these OPSCCs, and to a lesser extent several other high-risk types namely 18,31,33,35,39,45,51,52,56,58,59,66,68, 73 [13,14]. HPV is a small non-enveloped circular double stranded DNA virus that encodes three oncoproteins E5, E6, and E7 [15].…”

Training in molecular cytopathology testing

“…Gynaecological cytopathology molecular testing involves infectious disease tests such as those for neoplasia‐associated human papillomavirus and Chlamydia spp., and hence the detection of cancer precursors. This paper focuses on non‐gynaecological cytopathology molecular testing.…”

Decline in circulating viral and human tumor markers after resection of head and neck carcinoma

“…10,[17][18][19][20] In addition to somatic variants in human genes, viral genome levels in virally mediated cancers can be tracked over time, and results of such assays help assess tumor burden, clonal evolution or emerging treatment resistance. [21][22][23][24][25][26][27][28][29][30][31] Because primary tumor, regional recurrence, or distant metastases can each release cfDNA into the bloodstream, cfDNA analysis may reflect systemic heterogeneity in related clones in a more comprehensive fashion than is possible with tumor biopsy. 32 Prior studies of cell-free DNA have evaluated levels of either human gene variants or viral loads.…”