Scientists have made a great breakthrough in identifying the underlying genetic mutation that causes a rare form of kidney cancer called chromophobe renal cell carcinoma. While very little was known about the genetic basis of nonheredity manifestation of this type of cancer, this research will help doctors to identify the cause and devise appropriate interventions. The study was published Thursday in the journal Cancer Cell.

The research was a collaboration between universities around the world, including Baylor College of Medicine. It was funded by the National Institutes of Health's Cancer Genome Atlas Initiative. The researchers completed the sequence of the chromophobe renal cell carcinoma and even other rare types of cancers.

Chromophobe renal cell carcinoma accounts for five percent of all kidney cancer cases. Around 2,000 new cases are diagnosed each year in the United States. While the survival rate is high, advanced or metastatic cancers show poor prognosis.

"This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease," Dr. Kimryn Rathmell said in a statement, talking about how the new research would impact future cancer outcomes.

Samples of tumors were collected from 66 patients and were sequenced. Gene expression and epigenetic data were integrated with other types of data collected on these samples. After sequencing known genes and also DNA from mitochondria and from the entire genome, it was concluded that chromophobe renal cell carcinoma represents a distinct subtype of kidney cancers.

Chromosome Sequencing

Humans have 23 pairs of chromosomes, a total of 46 per cell. If the chromosomal structure gets manipulated in any way that leads to a loss of chromosomal material, it may result in cancer progression.

The study found that in a majority (86 percent) of the samples, one copy or a major part of chromosomes 1, 2, 6, 10, 13, and 17 were missing. When scientists looked for genes that were altered or missing, only two genes, TP53 and PTEN, were identified with a sizable frequency.

The team then conducted an extra analysis. In most genomic studies, only the exome that makes up about one percent of the genome is sequenced. This is a fastest way to look for changes that cause diseases. But in this study, the researchers sequenced the whole genome.

With whole exome analysis, scientists are just looking within the boundaries of known genes to see which are broken and may have caused the disease, explained Dr. Chad Creighton.

"However, when you look outside of the genes, there is much more going on," Creighton said. "For example, gene regulatory features of the genome can be altered."

The whole genome analysis revealed that there were a lot of structural rearrangements or breakpoints in the promoter region of a gene called TERT. The TERT gene provides instructions for making components of the telomerase enzyme.

Telomerase represent the "clock" of the cell, Creighton said. "This plays a critical role in cell division, and with many cancer cells, telomerase levels are really high and time never really runs out, which allows the cell to never die.

Since it was only the promoter region and not the whole gene that was affected “this malfunction is not picked up in whole exome analysis," Creighton said.

The study also highlights the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, say the authors.

This may alter the way research on other cancer studies are conducted said Creighton. "We need to survey the regulatory regions for other cancer types as well,” he said.

Source: Creighton C, Rathmell K, et al. Cancer Cell. 2014.