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Genome project uncovers new drivers, molecular features in papillary thyroid cancer
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SAN JUAN, Puerto Rico — An ongoing genome project offers a comprehensive dataset that confirms previous findings and provides new insight into the pathology, genomics and clinical features of papillary thyroid cancer, according to a presenter here.
The Cancer Genome Atlas (TCGA) included an analysis of more than 400 papillary thyroid carcinomas, with researchers aiming to identify rare mutations in a single histologic type and explain “dark matter” of unknown driver mutations through multiple platforms, Thomas Giordano, MD, a professor in anatomic pathology from the University of Michigan, said during his presentation.
“It is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing,” Giordano said. “This is a big problem for our field because if you genotype 100 thyroid cancers, you’re only going to find the usual BRAF, RAS mutations and fusions in 75% to 80%, so one of the goals was to find novel drivers.”
In doing so, the TCGA identified that 299 of 402 (74.4%) of the mutations were classified as BRAF (n=241), RAS (n=52) or EIF1AX (n=6), which is a rarely reported translational initiation factor. When they considered gene fusions of these classifications (n=49), that number grew to 348 of 402 (86.5%). The remaining 22 mutations (5.5%) were considered dark matter.
Next, they included copy number data, which showed no changes for many of the tumors, but there was a concentration of gains and losses shown after the fusions.
“We think these are complementary changes, mutually exclusive changes, that are housing driver mutations, and if you count those up, now you get up to almost 94%,” Giordano said. “At last count, I think we were down to five or six tumors that were dark, so I think we’ve succeeded in explaining this dark matter situation.”
Using a program called Absolute, researchers determined that most driver mutations are clonal, repeating frequently in tumor cells.
“There is much diversity within these BRAF tumors. There’s at least two, probably four, subtypes within that class. If you think about it, it probably explains some of the controversy in BRAF literature, depending on your cohort,” he said. “It also says we should probably stop looking for BRAF in isolation. It’s going to be BRAF plus other molecular features that really are most informative.”
Giordano explained that RAS-like and BRAF-like tumors are distinct across all platforms, and, in fact, RAS-like tumors are probably biologically closer to follicular carcinoma. This could lead to reinterpretation of portions of the older literature that groups papillary thyroid cancer into a single cohort, he explained.
“The overarching achievement of the TCGA project is that we created an outstanding clinical, pathologic and pangenomic dataset for broad use by everyone in the room,” Giordano said.
For more information:
Giordano T. Symposium: Molecular underpinnings of thyroid cancer development and growth. Presented at: the 83rd Annual Meeting of the American Thyroid Association; Oct. 16-20, 2013; San Juan, Puerto Rico.
TCGA Data Portal: https://tcga-data.nci.nih.gov/tcga
Disclosure: Giordano reports no relevant financial disclosures. This study was funded by the National Cancer Institute and the National Human Genome Research Institute.