Gene Study May Improve Thyroid Ca Management

Published: Oct 26, 2014 | Updated: Oct 27, 2014

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of
California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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, researcher Thomas 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 told MedPage 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 the RET 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 hypothyroidism cold feet 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 underactive thyroid symptoms 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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