romosome Conformation Capture (3C) can visualize where a regulatory element touches the DNA loop, providing a clue of where to look in more detail. Freedman also compares the number of RNA transcripts of genes in cells with and without a SNP, looking for correlations that suggest a candidate gene for further study. Applying these methods to prostate and breast cancer, Freedman identified novel genes not previously associated with cancer risk. He hopes such work can provide new genes to target therapeutically, and insights into prevention for those with inherited cancer risks.
A Promoter Linked to Melanoma
Several years ago, Levi Garraway’s team had generated enough whole genome sequences of melanoma that they decided to look for cancer risk mutations in the non-coding regions of the genome. A very simple first pass identified two novel single-DNA changes. One or the other mutation occurred in 17 of the 19 samples they could examine in detail, and they each occurred in the same promoter. “We didn’t believe it at first because the mutations were so prevalent,” recalls Garraway. “We had imagined that we might someday find a non-coding mutation that was as important as a coding mutation, but together these were more prevalent than the BRAF mutation in melanoma.”
But it began to make sense. They were somatic mutations, not hereditary, and they involved a C to T change in DNA base pairs – typical of the ultraviolet light-induced DNA damage that is important to melanoma development. Also, the mutations occurred in a promoter that regulates the TERT gene. TERT produces part of the telomerase enzyme that maintains the ends of chromosomes, called telomeres. Telomeres normally shorten with each cell cycle, eventually causing the cell to undergo apoptosis. By activating telomerase and maintaining these tips, cancer cells become “immortalized” – able to divide indefinitely.
The two mutations were also common in a larger sample set Garraway analyzed later (and in some bladder and liver cancers). But is telomerase dysregulation a target for new therapeutic intervention? “Telomerase has not been a major focus of anti-cancer drug development,” says Garraway, “but perhaps we should re-evaluate the premise empirically in cancers with mutations affecting telomerase.” In general, discovering links between regulatory elements and cancer risk promises to generate many new leads for researchers to follow in the coming years.
Full Speed Ahead
When targeted therapies were first introduced, the approval process for each took years. Now an existing drug can gain approval for a new cancer with a specific mutation relatively quickly. However, it often takes a national effort to identify enough patients with rare mutations to perform clinical trials properly. That difficulty motivated 15 institutions to form the Lung Cancer Mutation Consortium three years ago, with Bruce Johnson, MD (DFCI) as a co-principal investigator.
“The new paradigm in clinical trails is a genotype-specific and cancer-non-specific trial,” says David Kwiatkowski, who is planning such a trial to test an existing drug, the mTOR inhibitor everolimus, in cancers with mutations in either of two genes (TSC1 and 2) that regulate mTOR, a master kinase. Kwiatkowski first discovered one of these genes as the cause of an inherited cancer syndrome, Tuberous Sclerosis Complex, and the mutations have been identified in bladder cancer, a type of sarcoma, and pancreatic neuroendocrine tumors. Now the Cancer Genome Atlas (TCGA) project (Matthew Meyerson, MD, PhD (DFCI), co-principal investigator) has discovered low frequencies of these mutations in many types of cancer. Kwiatkowski wants to see if everolimus can be repurposed for treating patients with any cancer that has mutations in TSC1 or TSC2.
Like Moore’s law in electronics, technological innovations are helping cancer genetics research progress exponentially. Thanks in part to DF/HCC’s involvement in large collaborations like the Lung Cancer Mutation Consortium and TGCA, its discoveries are being rapidly translated into the clinic.
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