Study reveals a link between penile cancer and mitochondrial genome mutations | AGÊNCIA FAPESP

Study reveals a link between penile cancer and mitochondrial genome mutations Performed under the aegis of the Center for Cell-Based Therapy (CTC), the study is the first to investigate mitochondrial DNA in search of alterations associated with penile tumors (illustration: Molecular Biology Reports)

Study reveals a link between penile cancer and mitochondrial genome mutations

February 27, 2019

By Peter Moon  |  Agência FAPESP – A study published by Brazilian researchers in the journal Molecular Biology Reports suggests that mutations in mitochondrial genomes may favor the progression of penile cancer.

Penile tumors are rare in developed countries, accounting for approximately 0.4% of male malignant neoplasms in Europe and the United States. The incidence of penile tumors is much higher in Brazil. According to the National Cancer Institute (INCA), this type of tumor accounts for 2% of all cancer cases in Brazilian men.

“This is the first-ever study of mitochondrial genomes to investigate alterations that may be linked to penile cancer,” said Wilson Araújo da Silva Junior, a professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil and first author of the study, which was conducted at the Center for Cell-Based Therapy (CTC), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.

The most frequent type of penile cancer, accounting for 95% of all cases, is epidermoid carcinoma, also called spinocellular or squamous carcinoma. The cure rate is high when it is found early, but late diagnosis and delays in identifying the appropriate specific treatment are observed in more than 50% of cases.

The prevalence of penile cancer is highest among men aged 50 years or older who live in rural areas, although it is also found among younger men. It is associated with low socioeconomic status and limited education. Penile cancer is mainly caused by a lack of intimate hygiene and is more common among men with phimosis.

“Individuals who have surgery for phimosis are less likely to develop the disease,” said Rodolfo Borges dos Reis, a professor at FMRP-USP and principal author of the study.

Initially, there are no symptoms, but fluid discharge under the foreskin eventually causes a lesion in the glans, which may develop into a tumor and spread to other parts of the body.

In many cases, patients do not seek medical advice until the disease has reached an advanced stage, with an infected penile lesion that has invaded adjacent structures. Systemic therapy is ineffective at this stage, and surgery, possibly involving partial or total amputation, is the main form of treatment. Approximately one thousand penile amputations are performed annually in Brazil, according to national health system statistics (DATASUS).

Mitochondrial DNA

Mitochondria are organelles in eukaryotic cells that convert energy from food into a form cells can use. They are believed to have originated 2 billion years ago when certain microorganisms became symbiotic with invading bacteria.

In exchange for a constant food supply, scientists argue that these ancient bacteria began living inside the first eukaryotic cells, where they supplied energy. Over countless generations, the descendants of the invading bacteria became cellular organelles in the form of mitochondria.

Because of this evolutionary history, mitochondria retain vestiges of the independent ancestral bacteria they once were. The main relic is mitochondrial DNA, with some 16,500 base pairs comprising a unique genome. This differs starkly from the nuclear genome, which, in humans, has 23 pairs of chromosomes inherited from both parents and comprises some 3 billion base pairs. 

The main function of the mitochondria is to supply most of the energy used by cells. They do so via a process called cellular respiration. 

A single human cell contains some 10,000 mitochondria, each of which contains thousands of copies of its own DNA.

“The key trait that defines tumor cells is uncontrolled growth and multiplication,” Reis said. “Tumors need a great deal of energy in order to grow. Mitochondria are the source of this energy. It therefore makes sense to assume that tumor cells use mechanisms to preserve mitochondria. In this context, mitochondria and their genomes play a vital role.”

According to Reis, alterations in mitochondrial genomes are common in many types of tumors and are seen as regulators of the oxidative mechanism, with a direct impact on tumor progression.

“Mitochondria have been shown to play an important role in the progression of various types of tumors,” he said. “In the case of penile tumors, mitochondrial genome alterations hadn’t yet been described.”

Silva Junior stressed that the results of the study demonstrate an increase in the instability of mitochondrial DNA (mtDNA) in tumor tissue. “We analyzed mitochondrial genomes in penile carcinoma for the first time, with the aim of measuring heteroplasmy and mtDNA mutational load and content in these tumors,” he said. Heteroplasmy is the presence of more than one type of mitochondrial genome within a cell, some of which may have mtDNA mutations. 

The researchers used next-generation sequencing to analyze mitochondrial genomes in 13 penile tumors (from 13 patients) and 12 samples of healthy penile tissue and identified the mtDNA variants and the degree of heteroplasmy.

Mitochondrial genome sequencing revealed a reduction in the number of copies and a rise in the number of mtDNA variants in tumor tissue compared with normal penile tissue, confirming that mtDNA instability increases in penile tumors.

“We present a list of mitochondrial variants found in penile tumors, including five new variants found specifically in tumor tissue,” Reis said. “We also evaluated the pathogenicity of the variants, which is their capacity to contribute to the progression of the disease.” 

“We suggest that the reduction in the number of copies and increased mitochondrial genome instability may act together, contributing to an imbalance in the cellular metabolism of penile tumors,” Silva Junior said.

This is the first time a link has been established between penile cancer and mtDNA. A better understanding of mitochondrial biology may open up new possibilities for the treatment of penile cancer, the researchers note.

The article “Mitochondrial genome analysis in penile carcinoma” (doi: https://doi.org/10.1007/s11033-018-4197-5) by L.F. Araújo, A.T. Terra Jr., C.T.G. Sares, C.F.R. Sobreira, E.F. Faria, R.D. Machado, A.A. Rodrigues Jr., V.F. Muglia, W.A. Silva Jr. and R.B. Reis can be retrieved from: link.springer.com/article/10.1007%2Fs11033-018-4197-5

 

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