Genetic analysis of nearly 500 papillary thyroid carcinomas revealed new markers for aggressive tumors which could lead to more targeted treatments for patients with the cancer.
Researchers with The Cancer Genome Atlas (TCGA) identified several new cancer genes and several new variations of existing genes in their multiplatform analysis of 496 papillary thyroid carcinomas (PTCs), which account for about 80% of all thyroid cancers.
The findings suggest that thyroid cancers should be reclassified into molecular subtypes that better reflect their underlying signaling and differentiation properties, researcherThomas J. Giordano, MD, PhD, of the University of Michigan in Ann Arbor, and colleagues, wrote in the Oct. 23 issue of Cell.
They also provide new insight into how mutated cancer genes and other genomic alterations drive disease development, said Carolyn Hutter, PhD, who is program director in the division of genomic medicine for the National Human Genome Research Institute and a project team leader for TCGA.
TCGA researchers are conducing genetic analysis on 10,000 tumors from patients with 30 different malignancies to better understand the biological causes of cancer. The goal, Hutter said, is to give investigators the knowledge they need to develop therapies specific to a cancer's genomic profile.
Hutter told MedPage Today that a significant amount of knowledge can be gained by exploring the genomic and cellular alteration similarities and differences of diverse tumor types -- known as pan-cancer analysis.
"We are finding shared driver mutations across cancers, and this has therapeutic implications," she said. "I believe this research will inform the treatment of many cancers in the future."
Thyroid Cancer Incidence Increasing
Thyroid cancer incidence has increased threefold over the last 3 decades, and the prevalence of different genetic profiles has also changed during this period, the researchers wrote.
More than 20,000 new cases of PTC are diagnosed in the U.S. each year, and overtreatment of the highly curable cancer is an increasing concern, Giordano toldMedPage Today. The cancer is treated with surgery, thyroid hormone, and radiation, with a 5-year survival rate of over 95%.
Previous genetic studies suggest a high frequency (70%) of activating somatic alterations of genes encoding effectors in the mitogen-activated protein kinase (MAPK) signaling pathway, including point mutations of BRAF and the RAS genes, as well as fusions of theRET and NTRK1 tyrosine kinases, the researchers noted.
MAPK pathway alterations have been shown to be strongly associated with distinct clinicopathologic characteristics, and gene expression and DNA methylation profiles. Mutations in members of the P13K pathway, such as PTEN, PIK3CA and AKT1 have also been reported at low frequencies.
As in the other TCGA studies, the analysis of the 496 PTC tumors examined mutations, copy number alterations, mRNA expression, miR expression, protein expression and DNA methylation.
Genetic Cause of Most PTCs Now Known
The analysis confirmed that PTCs are driven mainly by mutations in BRAF, primarily the V600E mutation, or in RAS. The analysis also showed that BRAF-driven tumors have a broader range of genetic complexity than has previously been appreciated.
"We basically defined all the mutations that occur in papillary thyroid cancer, which has a lot of implications for molecular diagnostics and other areas," Giordano said.
Because the BRAF and RAS are mutually exclusive in PTC but share the same signal pathway, the researchers were able to look for gene expression signatures that reflected whether a tumor was more BRAF- or RAS-like.
They observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2.
"The relative low overall density of somatic mutations may be the biological basis for the indolent clinical behavior of PTC," the researchers wrote, adding that the discovery of new driver alterations for the cancer reduces the percentage of PTC cases with an unknown oncogenic driver from 25% to less than 4%, which could have a major impact on preoperative decision-making.
"This paper has implications for who need surgery and for how much surgery they need," Giordano said. "A lot of people in molecular diagnostics are working on this, and now that we have a fuller genomic landscape those molecular tests should become much more informative."
Finding Should Lead to Less Overtreatment
The researchers wrote that molecular testing of mutation hotspots, rearrangements, and gene expression through fine-needle aspiration of specimens is now used in clinical practice in an effort to reduce thyroidectomies performed for benign nodules and tumors and determining the extent of initial surgery (lobectomy versus total thyroidectomy).
Beyond the driver mutations, the researchers identified individual genes (CHEK2, ATM, and TERT) and sets of functionally related genes (chromatin remodeling) with alterations or expression patterns (miR-21 and miR-146b) that define clinically relevant subclasses of papillary thyroid carcinoma and may contribute to loss of differentiation and tumor progression.
"Specifically, increased expression of miR-21 was associated with a known aggressive form of PTC (tall cell variant) and may be a critical event in its pathogenesis," they wrote. "Similarly, TERT promoter mutations identified a subset of aggressive, less-differentiated PTCs, consistent with recent reports. Our study also indicates that BRAFV600E PTC represents a diverse group of tumors, consisting of at least four molecular subtypes, with variable degrees of thyroid differentiation."
The researchers concluded that BRAFV600E PTC should not be considered a homogeneous group in clinical studies and that future studies should include molecular components designed to capture the genetic diversity among PTCs.
"Our paper really cements the notion that, moving forward, clinical trials of thyroid cancer must capture the underlying genetic complexity of individual tumors," Giordano said. "Without this knowledge it will be difficult to fully interpret the results."
PTC Good Model for Studying BRAF and RAS
The demonstration of significant signaling differences in RAS-driven and BRAFv600E-driven PTCs and the relative simplicity of the PTC genome, with dominant mutually exclusive driving events, makes PTC an ideal model for studying the sequencing consequences of BRAF and RAS mutations, he added.
A main conclusion from the analysis is that RAS-driven and BRAFv600E-driven PTCs are dramatically different in their genomic, epigenomic, and proteomic profiles, the researchers noted.
"RAS-driven tumors are so fundamentally different from tumors that have BRAF600E or other BRAF-like mutations that we concluded that they really don't belong together under the big diagnosis of PTC," Giordano said.
This finding is consistent with the known histologic differences and the published literature, but the researchers noted that the breadth and depth of their findings have wider implications for basic pathobiology, tumor classification schemes, and traditional and targeted therapies.
PTC Isn't a 'Uniform, Homogenous Cancer'
Based on the strength of the findings, Giordano and colleagues wrote that pathologic reclassification of follicular-patterned thyroid lesions is justified.
"A refined classification scheme that more accurately reflects the genotypic and phenotypic differences between and within (RAS- and BRAFv600E-driven) PTC would lead to more precise surgical and medical therapy, especially as thyroid cancer therapy enters the realm of precision medicine," they wrote.
Giordano said some of the findings from the analysis are already being incorporated into new PTC assays.
"Our paper clearly shows at least four molecular subtypes, so it is probably no longer appropriate to consider PTC a uniform, homogeneous type of cancer," he told MedPage Today.
TCGA research is funded by the National Institutes of Health.
The researchers declared no relevant relationships with industry.
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Primary source: Cell
