Brazilian study describes group of genes associated with kidney cancer recurrence

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Agência FAPESP* –By Karina Toledo
Agência FAPESP – Universidade de São Paulo (USP) scientists recently described a group of non-coding protein genes associated with cases of kidney cancer recurrence. The article was published in Molecular Cancer magazine.
“For the first time, we showed that the non-coding RNAs can be related to the biology of a more aggressive tumor, and may therefore be potential targets for new medications,” highlighted Sergio Verjovski-Almeida, researcher at the USP’s Chemistry Institute and coordinator of the FAPESP-funded study.
Until recently, scientists considered the entire genome that does not contain information for protein production – approximately 98% of the genetic code – to be “junk DNA.” More recent studies have shown, however, that RNA expression occurs in some of these regions, modulating the functioning of neighboring genes.
The study coordinated by Verjovski-Almeida is focused on the so-called long intronic noncoding genes – those located in the same region as a coding gene but on the opposite strand of DNA.
Through a technique known as DNA microarray, which allows the evaluation of the expression of thousands of genes simultaneously, the researchers compared the tumor tissues of seven patients who had kidney cancer recurrences within the first five years of treatment with tumor tissues from 11 patients who remained free of the disease within this period. They also compared the tumor tissues of these 18 patients with healthy tissues from the regions adjacent to the tumors.
“The standard microarray method analyzes only the expression of protein coding genes. We have to design our own test to make it sensitive to the non-coding sequences,” explained Verjovski-Almeida.
The comparison between tumor and non-tumor tissue revealed 29 noncoding intronic genes that were differentially expressed in the two groups. Another 26 noncoding genes had altered expression in the comparison between the patients with and without recurrence. Only two non-coding genes appeared in both analyses. All the patients were in treatment at the National Cancer Institute (INCA) and had one kidney that had been surgically removed.
“The altered expression in these genes could be indicative of the aggressiveness of the tumor. Still, these findings must be validated in a larger independent group of patients so that they can be used as markers,” explained the researcher.
Correlations
The next step in the study was to verify which expressed non-coding intronic genes were correlated – positively or negatively – to the expression of coding genes.
“The idea was to identify whether the increase in the expression of non-coding genes would increase or decrease the expression of coding genes. We conducted analysis on the kidney tumor tissue and with prostate and liver tumors to compare,” explained Verjovski-Almeida.
The analysis showed the relationship between 700 coding genes and 109 noncoding genes. This means that each noncoding intronic gene was regulating the functioning of, on average, seven coding genes in the tissue analyzed.
“Roughly 22% of these noncoding genes are regulating the functions of coding genes at the same locus, or, rather, the same region of the genome, but on the opposite strand of DNA. The other 78% were regulating the functions of genes located in other regions of the genome,” affirmed Verjovski-Almeida.
The analysis further suggests that these noncoding genes indirectly affect important renal functions, such as the transportation of ions and protons, cellular adhesion, stress response and inflammatory processes.
“It is a complex network. When gene expression is altered, it modifies several of the organ’s critical functions. New studies are needed to understand why this set of noncoding genes is being expressed differently in the tumor tissues. Only then can we think about interventions to increase the expression of those that are diminished and vice versa,” evaluates the researcher.
According to Verjovski-Almeida, however, studies of this type are impeded by the difficulty of obtaining patient samples. In addition to the relative rarity of renal cancer, it is not standard practice for doctors in the area to store tissue for future research.
“What we intend to do at first is to determine whether the genes known to be involved in cancer are being regulated by non-coding genes. Several studies show, for example, that RAB31 and RAB25 coding gene expression is reduced in cancer patients. There is a possibility that they are being regulated by noncoding genes at the same locus. We will explore cases like these,” said Verjovski-Almeida.

<p><b>By Karina Toledo</b></p>
<p><b>Agência FAPESP</b> – Universidade de São Paulo (USP) scientists recently described a group of non-coding protein genes associated with cases of kidney cancer recurrence. The <b><a href="http://www.molecular-cancer.com/content/12/1/140" target="_blank">article</a></b> was published in <i>Molecular Cancer</i> magazine.</p>
<p>“For the first time, we showed that the non-coding RNAs can be related to the biology of a more aggressive tumor, and may therefore be potential targets for new medications,” highlighted Sergio Verjovski-Almeida, researcher at the USP’s Chemistry Institute and coordinator of the <b><a href="http://www.bv.fapesp.br/en/auxilios/2125/functional-characterizaton-of-intronic-non-coding-rnas-expressed-in-the-human-genome/" target="_blank">FAPESP-funded study</a></b>.</p>
<p>Until recently, scientists considered the entire genome that does not contain information for protein production – approximately 98% of the genetic code – to be “junk DNA.” More recent studies have shown, however, that RNA expression occurs in some of these regions, modulating the functioning of neighboring genes.</p>
<p>The study coordinated by Verjovski-Almeida is focused on the so-called long intronic noncoding genes – those located in the same region as a coding gene but on the opposite strand of DNA.</p>
<p>Through a technique known as DNA microarray, which allows the evaluation of the expression of thousands of genes simultaneously, the researchers compared the tumor tissues of seven patients who had kidney cancer recurrences within the first five years of treatment with tumor tissues from 11 patients who remained free of the disease within this period. They also compared the tumor tissues of these 18 patients with healthy tissues from the regions adjacent to the tumors.</p>
<p>“The standard microarray method analyzes only the expression of protein coding genes. We have to design our own test to make it sensitive to the non-coding sequences,” explained Verjovski-Almeida.</p>
<p>The comparison between tumor and non-tumor tissue revealed 29 noncoding intronic genes that were differentially expressed in the two groups. Another 26 noncoding genes had altered expression in the comparison between the patients with and without recurrence. Only two non-coding genes appeared in both analyses. All the patients were in treatment at the National Cancer Institute (INCA) and had one kidney that had been surgically removed.</p>
<p>“The altered expression in these genes could be indicative of the aggressiveness of the tumor. Still, these findings must be validated in a larger independent group of patients so that they can be used as markers,” explained the researcher.</p>
<p><b>Correlations</b></p>
<p>The next step in the study was to verify which expressed non-coding intronic genes were correlated – positively or negatively – to the expression of coding genes.</p>
<p>“The idea was to identify whether the increase in the expression of non-coding genes would increase or decrease the expression of coding genes. We conducted analysis on the kidney tumor tissue and with prostate and liver tumors to compare,” explained Verjovski-Almeida.</p>
<p>The analysis showed the relationship between 700 coding genes and 109 noncoding genes. This means that each noncoding intronic gene was regulating the functioning of, on average, seven coding genes in the tissue analyzed.</p>
<p>“Roughly 22% of these noncoding genes are regulating the functions of coding genes at the same locus, or, rather, the same region of the genome, but on the opposite strand of DNA. The other 78% were regulating the functions of genes located in other regions of the genome,” affirmed Verjovski-Almeida.</p>
<p>The analysis further suggests that these noncoding genes indirectly affect important renal functions, such as the transportation of ions and protons, cellular adhesion, stress response and inflammatory processes.</p>
<p>“It is a complex network. When gene expression is altered, it modifies several of the organ’s critical functions. New studies are needed to understand why this set of noncoding genes is being expressed differently in the tumor tissues. Only then can we think about interventions to increase the expression of those that are diminished and vice versa,” evaluates the researcher.</p>
<p>According to Verjovski-Almeida, however, studies of this type are impeded by the difficulty of obtaining patient samples. In addition to the relative rarity of renal cancer, it is not standard practice for doctors in the area to store tissue for future research.</p>
<p>“What we intend to do at first is to determine whether the genes known to be involved in cancer are being regulated by non-coding genes. Several studies show, for example, that RAB31 and RAB25 coding gene expression is reduced in cancer patients. There is a possibility that they are being regulated by noncoding genes at the same locus. We will explore cases like these,” said Verjovski-Almeida.</p>