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Michigan Team Identifies Targetable Mutations in Penile Cancers

NEW YORK (GenomeWeb) – Researchers from the University of Michigan and Thermo Fisher Scientific have identified mutations in genes that can be targeted with approved drugs in 43 patients with penile cancer, using a next-generation sequencing panel.

The team reported in the journal Cancer Research this week that its work was one of the first genomic studies of penile squamous cell carcinoma (PeSCCA) and said that a better understanding of the molecular alterations underlying this type of cancer, for which there are currently limited targeted treatment options,should help shed light on potential drug strategies.

"Comprehensive profiling of somatic genomic alterations in PeSCCA has not been reported," the authors wrote, and as such, "the key molecular alterations driving [penile cancer] development and potential therapeutic targets are incompletely understood."

Although around 80 percent of penile cancers can be cured with surgery, advanced or aggressive forms of the disease require drug treatment, but there are limited options and few treatment guidelines for these patients.

The UMich team performed targeted sequencing using Thermo's 126-gene Oncomine Comprehensive Panel, which the company provided for the study. Sequencing was performed on the Ion Torrent PGM or Proton sequencing system.

The researchers analyzed 60 formalin-fixed paraffin-embedded samples from 43 patients with penile cancer, including 14 patients who had matched metastatic samples. They also analyzed the samples for human papillomavirus, a known risk factor, and performed immunohistochemistry for p16 and EGFR. EGFR overexpression has been found in a large percentage of penile cancer patients and p16 expression is often correlated with HPV infection.

The patients' primary tumors spanned several clinical stages of the disease, with 12 patients classified as clinical stage I, 13 as stage II, three as stage III, and 14 as stage IV. One patient only had a metastatic sample available.

After sequencing, the researchers identified a total of 94 somatic point mutations. The genes TP53, CDKN2A, PIK3CA, and HRAS were the most frequently mutated, with mutations in 29, 20, nine, and eight samples, respectively. The researchers also performed a copy number analysis, identifying 54 copy number gains and 18 copy number losses. They found gains most frequently in MYC, CCND1, SOX2, ATP11B, EGFR, and TERT, while 72 percent of copy number losses involved CDKN2A.

Looking at the 14 cases that had both primary tumor and metastatic samples, the researchers noted that the somatic SNVs and indels were highly concordant between the samples, while the copy number alterations matched significantly less frequently.

The researchers identified HPV, which is known to play a role in the pathogenesis of penile cancer, in five patients. Interestingly, the cases in which HPV was present had fewer mutations, averaging just one per sample, as opposed to an average of two per sample in HPV-negative cases.

While the number of mutations per tumor did not correlate with clinical status or tumor grade, the researchers did find that having more mutations in the most frequently mutated genes — CDKN2A, EGFR, MYC, HRAS, or TP53 — was associated with a more advanced clinical stage. Amplification in MYC and CCND1 was also associated with a shorter time to progression, while p16 expression was correlated with a better outcome.

Finally, the team wanted to look at potentially targetable mutations.

Four patients had EGFR amplifications and one had a CDK4 amplification, both of which confer eligibility for clinical trials.

Previous studies of penile cancer have found that overexpression of EGFR is common, and there has been some investigational use of anti-EGFR therapies in advanced cases, but with limited results. Looking deeper into EGFR amplification and overexpression, the researchers performed EGFR immunohistochemistry on samples from five patients with both primary and metastatic samples and found EGFR to be strongly expressed in all samples. Interestingly, however, expression did not always correlate with EGFR copy number status.

The researchers hypothesized that this discordance between copy number and expression may explain why anti-EGFR therapies have had limited success in penile cancer patients and suggested that perhaps tumors with EGFR amplification may be more sensitive to EGFR targeting than those without.

In addition, five patients had activating HRAS mutations, which may also "complicate EGFR-targeted therapy efforts," as such mutations have been thought to confer resistance to EGFR-based therapies in other cancers.

The study "provides a roadmap to design better, more informed trials for penile cancer," Scott Tomlins, senior author of the study and an assistant professor of pathology and urology at the University of Michigan Medical School, said in a statement. "This is the basic knowledge we need to open the door to more individualized trials and treatments in the future."