High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer

Glenn WK, Ngan CC, Amos TG, Edwards RJ, Swift J, Lutze-Mann L, Shang F, Whitaker NJ & Lawson JS (2017): High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer. Infectious Agents and Cancer 12:46.

Abstract

Background. Although high risk HPVs are associated with an increased risk of prostate cancer it is not known if they have a causal role. The purpose of this study is to investigate the potential role of human papilloma viruses (HPVs) in prostate cancer. The aims are (i) to investigate the presence and confirm the identity of high risk HPVs in benign prostate tissues prior to the development of HPV positive prostate cancer in the same patients, and (ii) to determine if HPVs are biologically active.

Methods. We used polymerase chain reaction (PCR) to identify HPVs in specimens from 52 Australian men with benign prostate biopsies who 1 to 10 years later developed prostate cancer. Immunohistochemistry (IHC) was used to assess the expression of HPV E7 oncoproteins, cytokeratin and prostate specific antigen (PSA).

We used RNASeq data from The Cancer Genome Atlas (TCGA) to identify possible HPV RNA sequences in prostate cancer.

Results. HPV screening using standard PCR was conducted on 28 of the 52 sets of benign and later prostate cancers. HPV L1 genes were identified in 13 (46%) benign and 8 (29%) of 28 later prostate cancers in the same patients. HPV E7 genes were identified in 23 (82%) benign and 19 (68%) of 28 subsequent prostate cancers in the same patients. The same HPV types were present in both the benign and subsequent prostate cancers in 9 sets of specimens. HPV type 16 was identified in 15% of benign and 3% of prostate cancers. HPV type 18 was identified in 26% of benign and 16% of prostate cancers. Small numbers of HPV types 45, 47, 76 and 115 were also identified.

High confidence RNA-Seq evidence for high risk HPV types 16 and 18 was identified in 12 (2%) of the 502 TCGA prostate cancer transcriptomes.

High risk HPV E7 oncoprotein was positively expressed in 23 (82%) of 28 benign prostate specimens but only in 8 (29%) of 28 of the later prostate cancer specimens. This difference is statistically significant (p = 0.001). Prostate specific antigen (PSA) was more highly expressed in 26 (50%) of 52 prostate cancer specimens as compared to prior benign prostate specimens in the same patients.

Conclusions. High risk HPVs are present in benign prostate tissues prior to the development of HPV positive prostate cancer. There is a significantly higher expression of HPV E7 oncoproteins in benign prostate tissues as compared to late prostate cancer that subsequently developed in the same patients. This observation suggests that HPV oncogenic activity is an early phenomenon in a majority of prostate oncogenesis. TCGA RNA-Seq data suggests that HPV is biologically active in some prostate tumour samples.

Emeritus Professor Jim Lawson has this to say about the study:

“Human papilloma viruses are the cause of cervical cancer in women. These viruses are sexually transmitted. Infections by human papilloma viruses can be prevented by effective vaccines including the Australian developed Gardosil.

Scientists from the University of New South Wales, Sydney, Australia, have identified high risk human papilloma viruses in normal prostate tissues 2 to 12 years before the development of human papilloma virus positive prostate cancer. While the scientists do not claim this is evidence that human papilloma viruses are a direct cause of prostate cancer, they advise that it is prudent for both men and women to act with caution.

Human papilloma viruses are present in semen in over 15% of men and can be readily transmitted during sexual activities.

Vaccines such as the Australian developed Gardosil, are safe and effective in preventing infections by human papilloma viruses. The University of New South Wales scientists strongly encourage both young men and women to prevent human papilloma virus infections by vaccination at a young age.”

#ABACBS Poster FF6: Evidence for viral causes of cancer in prostate cancer transcriptomes and genomes

Timothy G. Amos, James S. Lawson, Wendy K. Glenn, Noel J. Whitaker & Richard J. Edwards. http://f1000research.com/posters/4-1023.

Abstract

Viruses are known to cause 10-15% of human cancers. Some ongoing viral infections such as HPV in cervical cancer can be easily detected in the cancer transcriptome. However, in other situations viruses contribute to cancer causation without sustained high expression levels. PCR has detected HPV in prostate cancers but RNA-Seq has not shown strong evidence of continuing infections. We analysed prostate cancer transcriptomes and genomes from The Cancer Genome Atlas to further investigate HPV’s role in prostate cancer causation. Previous studies have filtered out all reads that might not be viral and then set thresholds for real infections by comparing to positive controls. In contrast, we found all possible viral reads and then evaluated multiple streams of evidence that they were genuine. Sequences were evaluated on the uniqueness of alignments to human, viral and vector sequences. They were also evaluated for sequence complexity, sequence quality, alignment quality, relative alignment locations of paired-end reads and the presence of chimeric reads that indicate viral integration sites. By screening cancer transcriptomes and genomes against all viruses in the NCBI database (c. N = 5766), including non-human viruses, we are also able to compare the strength of evidence against known false positives. We discuss the results of 22 viral candidates for oncogenesis in 558 prostate cancer paired RNA-Seq and WGS datasets.

ABiC2014 posters on F1000Posters

Better late than never, both posters from ABiC2014 are now on F1000Posters, along with many other great posters from the conference:

Richard J Edwards, Ranjeeta Menon, Nicolas Palopoli & Jason FH Wong (2015) Molecular mimicry in viruses and cancer. F1000Posters 6: 101.

Nicolas Palopoli & Richard J Edwards (2014) Computational prediction of protein interaction motifs using interaction networks and 3-dimensional structures. F1000Posters 5: 1682.

#ABiC14 Poster 45: Molecular mimicry in viruses and cancer

Richard J Edwards, Ranjeeta Menon, Nicolas Palopoli & Jason WH Wong

Abstract

Molecular mimicry is a well-established example of convergent evolution by which viruses evolve protein motifs that interact with host molecular machinery to hijack cellular functions. These short linear motifs (SLiMs) have only a handful of critical positions and a single point mutation is often sufficient to create or destroy a motif occurrence. This may have direct effects, such as eliminating a key regulatory interaction, or more subtle indirect effects by altering/blocking neighbouring interactions. There is much overlap in the breakdown of regulation caused by viruses and cancers - including oncogenic viruses - and so it is likely that many cancers are exploiting similar molecular mimicry mechanisms of protein interaction motifs during tumour development and progression.

We are combining publicly available datasets of host-host and host-pathogen PPI with recently developed tools from the SLiMSuite package to (1) identify novel candidates for viral mimicry of known host SLiMs, and (2) predict entirely new SLiM classes. In each case, signals of convergent evolution are identified using statistical over-representation of motifs in unrelated proteins. We are also using SLiM analysis tools to identify putative gain- and loss-of-function mutations from public cancer mutation databases. SLiM predictions and mutations will be placed in context using the human protein-protein interaction network and cross-referenced to known viral molecular mimicry and proteins/pathways affected in cancer. Simulated mutation data will be used to test for possible enrichment of mutations that create or destroy SLiMs.

Keywords: molecular mimicry, cancer, viruses, protein-protein interactions, short linear motifs, SLiMs