As link grows stronger, HPV and cervical cancer cytology testing is called into question.
Vol. 23 • Issue 4 • Page 16
An international team of researchers injected another glob of scientific super glue into the connection between human papillomavirus (HPV) and cervical cancer in their study on the “Landscape of Genomic Alterations in Cervical Carcinomas.”1
“The extent to which the study underscores the importance of HPV in cervical cancer makes it significant to diagnostics,” said Akinyemi Ojesina, co-first author and a Harvard Medical School postdoctoral fellow in Matthew Meyerson’s pathology and medical oncology lab at the Broad Institute, Cambridge, Mass., and Dana-Farber Cancer Institute, Boston. “We were able to identify in a comprehensive manner a fuller repertoire of mutations that are found in cervical cancer to a greater degree than previously known. These characterizations led to the identification of potential therapeutic targets. We also identified a phenomenon that suggests widespread gene activation by HPV integration into the human genome.”
The researchers, from the United States, Mexico and Norway, completed an extensive genome analysis of cervical cancer in two diverse patient populations. Whole exome sequencing (analyzing the genetic code in the protein regions of the genome) was conducted on specimens from 115 patients with cervical cancer from Norway and Mexico. Whole genome sequencing (examining the genetic code across the entire genome) or transcriptome sequencing (examining gene expression) was also conducted in some cases.
The team then compared genomic data from cervical cancer tumors with genomic data from healthy tissue from the same individual to determine what may have gone wrong in the genome to allow the cancer to develop.
“What we are seeing is that, in two different populations, the causes of cervical cancer are similar and, fundamentally in both cases, it comes down to HPV-genome interaction,” said Meyerson via information supplied jointly by Dana-Farber and Broad Institute.
“We identified three sets of genes in which we have mutations,” Ojesina told ADVANCE. “First, we identified mutations in genes that have previously been shown to be mutated in cervical cancer.
“Next, we identified mutations in genes that have previously been shown to be mutated in other cancers, but not in cervical cancer. In particular, ERBB2 (Her-2) has been previously connected to breast cancer. This suggests that a subset of cervical cancer patients could be candidates for clinical trials involving ERBB2 inhibitors, which are available and FDA-approved. It is an exciting finding that could be translatable to the clinic,” said Ojesina. “And finally, we found mutations in genes that were not previously shown to be mutated in any cancer – like the MAPK1 gene and the HLA-B gene.”
MAPK1 is one of the final steps in the MAP kinase signaling pathway. Mutations in other genes in the pathway have been known to drive cancer, but this is the first time that MAPK1 itself has been found to be mutated. The finding opens up the possibility that MAPK1 may be a viable therapeutic target.
Another key finding outlined in information provided by Dana-Farber and Broad Institute was the prevalence of mutations in genes affecting the immune system. Mutations in the gene HLA-A were previously found to drive squamous cell lung cancer. In this study, another gene in the same complex, HLA-B, was found to be commonly mutated in cervical squamous cell carcinoma.
Gene Expression Amplified
Finally, transcriptome sequencing, which allowed the team to analyze gene expression, shed some light on how HPV is driving cervical cancer.
“We identified that there was a huge amount of overlap between the site in which HPV integrates and the sites of genome amplification,” explained Ojesina.
The study examined where, in the genome, HPV inserted itself and found that HPV integration sites were associated with higher levels of gene expression and were often amplified, resulting in many copies of those sections of the genome. This connection between HPV integration and gene expression suggests that HPV may be driving cancer by promoting and elevating the activity of mutated genes, according to Ojesina.
Every shred of evidence detailing the ways in which HPV links to cervical cancer is crucial in a global effort to diagnose and treat HPV and cervical cancer. While the human toll is far greater in developing countries, the CDC reports that each year, there are an estimated 26,000 HPV-attributable cancers in the United States. The CDC also estimates that $8 billion are spent each year on direct medical costs for preventing and treating HPV-associated disease.
And while available HPV vaccines prevent infection from the HPV types that cause about 70% of cervical cancers and the majority of other HPV-attributable cancers, current vaccines do not protect against all HPV types. In addition, adoption of the vaccine remains suboptimal in countries where vaccination is not bolstered by in-school programs (the U.S., France, Germany, the Netherlands, among others).2 So even in light of the preventive promise of vaccines, effective screening for HPV and cervical cancer remain essential for human health and the fiscal survival of American healthcare.
Limits of Cytology Screening
A paper published this year in the Annals of Oncology2 noted that while “cytology-based screening has led to a reduction in the incidence of cervical cancer in western countries, the sensitivity of cytology for the detection of high-grade precursor lesions or cervical cancer is limited; therefore, repeated testing is necessary.. Additionally, adenocarcinomas and its precursors are often missed by cytology. Consequently there is a need for a better screening test.”
The authors said that insights (such as those gained in the previously noted research) making a water-tight connection between HPV and cervical cancer has led to the development of molecular tests specifically for high-risk HPV (hrHPV).
In their review of literature pertaining to studies on the effectiveness of hrHPV tests – both DNA assays and E6/E7 mRNA assays – the authors said that available DNA tests (such as the digene HC2 HPV DNA Test, cobas 4800 from Roche, Real-Time (RT) PCR by Abbott Molecular, Papillocheck from Bio Greiner, as well as GenProbe’s mRNA APTIMA HPV assay) perform with such sensitivity and specificity as to be clinically validated for primary hrHPV-based cervical cancer screening.
The authors concluded that “all the evidence collected so far suggests that the time has come for the implementation of hrHPV testing as a primary screening test, as it provides a superior protection against cervical (pre-cancerous) lesions compared with cytology . Collectively, these data show that the time has come to implement primary hrHPV testing in population-based cervical screening, thereby offering women maximum protection against high-grade CIN with less uncertainty and fewer screening rounds.”
- Ojesina A et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014. DOI: 10.1038/nature12881
- Dijkstra M et al. Cervical cancer screening: on the way to a shift from cytology to full molecular screening.Annals of Oncology 00: 1-9, 2014. DOI: 10.1093/annonc/mdt538