DDNews Cancer Research Exclusive: Turning an eye to TERT

Chromophobe renal cell carcinoma has an incidence of just 2,000 new cases diagnosed in the United States each year. While the only treatment option for these patients is surgery, most patients do survive this disease. As noted on the TCGA website, chromophobe renal cell carcinoma “forms in the cells lining the small tubules in the kidney” that help filter waste from the blood.

The researchers sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center, sequencing known genes as well as DNA from mitochondria and from the entire genome. They found that 86 percent of the sequenced samples were missing one copy or a major part of chromosomes 1, 2, 6, 10, 13 and 17, with 12 to 58 percent presenting with losses of chromosomes 3, 5, 8, 9, 11, 18 and 21. In terms of mutated or missing genes, TP53 and PTEN came up fairly frequently; the former was frequently mutated in 32 percent of cases (21 of the 66 samples), while the latter was frequently mutated in 9 percent (6 of 66) nonsilent mutations detected. According to the report, “No other genes were found to be mutated at a frequency higher than 5 percent, though mutations involving cancer-relevant genes were found at lower frequencies.”

Dr. Chad Creighton, associate professor of medicine and a biostatistician in the NCI-designated Dan L. Duncan Cancer Center at Baylor, says that while many other cancers present with copy number alterations, “the loss of the entire chromosome is somewhat unusual.”

“Although most patients are reassured when the pathology of their kidney tumor comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said Dr. Kimryn Rathmell, associate professor of hematology and oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co-senior author on the study. “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.”

Thanks to their sequencing of both the genome and exome, the researchers also saw a significant number of structural rearrangements or breakpoints that involve the promoter region of the TERT gene, which is responsible for encoding the most important part of the telomerase complex. As noted in the report, “The observed TERT promoter rearrangements may result from genomic instability in precancerous cells undergoing the crisis stage of immortalization, leading to activated telomerase,” though Creighton says further research into this discovery is necessary.

“The TERT gene is known to be misregulated in many cancers, although the reason for that has not been understood in many cases. So I think our study would point to a new mechanism by which the TERT gene is turned on in cancers, because it’s something that does not affect the gene itself, it’s something next to the gene, where there’s DNA damage,” says Creighton, who is the lead and corresponding author on the report. “And TERT is important in that it has a key component of telomerase, which is basically something that allows for cell division. It’s supposed to run out when the cells are ready to die, but in some cancer cells, there’s too much telomerase, so the cancer cells never die. And so in some of our cancers, there was high levels of TERT, and the reason for that seems to be this DNA damage event next to the gene, which seems to alter the regulation or how much that gene is turned on.”

Their in-depth analysis is what let them identify these effects, said Creighton, because the alterations were in the promoter region rather than the gene, and “Since there isn’t a breakdown in the actual gene, this malfunction is not picked up in whole exome analysis.”

“Elsewhere, rearrangement of DNA sequences upstream of TERT has been reported in immortalized, nontumorigenic fibroblasts, leading to activated telomerase in cells surviving the crisis stage of immortalization (Zhao et al., 2009), which involves chromosomal instability and rearrangements due to loss of telomere capping activity; in the setting of human cancer, this would suggest that TERT-associated rearrangements would be involved in many cases at an early stage in tumorigenesis,” the report adds.

“The Cancer Genome Atlas is a federally funded national effort that has already completed the sequence of many major types of cancer (breast, lung, ovarian, for example), but this project is now branching out to sequence more rare types of cancer,” said Creighton. “The idea is that with a better understanding of these more rare types of cancers, we gain new insight that might be relevant to how we study other types of cancer. The findings in this study are a perfect example of that.”