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TERT promoter and BRAF mutation co-existence defines ‘most aggressive subgroup of PTC’
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SAN JUAN, Puerto Rico — The co-existence of BRAF mutation and promoter mutation in the telomerase reverse transcriptase gene found in some papillary thyroid cancer may cause the most aggressive subgroup, a presenter said here.
“If you look at the TERT [telomerase reverse transcriptase] C228T and BRAF V600E, there was a significant association. We think the two together promote progression and recurrence of [papillary thyroid cancer] and define a highly — perhaps the most — aggressive subgroup of [papillary thyroid cancer],” said Mingzhao Xing, MD, of the division of endocrinology, diabetes and metabolism at Johns Hopkins University School of Medicine. “This is an exciting area. The discovery of [telomerase reverse transcriptase] promoter mutation in thyroid cancer this year opens an important new thyroid cancer research area of potentially high biological and clinical significance.”
Mingzhao Xing
Researchers looked at 402 patients with papillary thyroid cancer (PTC; 290 female, 112 male), aged 12 to 85 years (mean age, 46.1 ± 13.8 years), with a clinical follow-up for a median of 23 months. They analyzed BRAF V600E and telomerase reverse transcriptase (TERT) promoter by sequencing of genomic DNA from primary tumors, then analyzed the relationship of mutations with clinicopathological outcomes of PTC.
Previously seen in melanoma, Xing said TERT C228T occurred more frequently in tumors positive for BRAF V600E. Of the 224 BRAF-negative tumors, only 18 (7.4%) tested positive for TERT C228T, whereas of the 137 BRAF-positive tumors, 23 (14.4%) were also positive for TERT C228T (P = .024).
When compared with wild-type tumors without either mutation (n=224), tumors with either BRAF (n=137) or TERT (n=18) alone had different progressive factors. BRAF-positive tumors had a higher rate of lymph node metastases, extrathyroidal invasion and overall recurrence with 42.3%, 22.9% and 20.4%, respectively, compared with 22.3%, 12.1% and 10.3% in wild-type tumors (P<.001; P=.007; P=.007, respectively). TERT-positive tumors also had higher rate of lymph node metastases at 50% compared with wild-type tumors at 22.3% (P=.009).
When the two mutations co-existed in certain tumors (n=23), they displayed even greater progressive factors compared with the wild-type group: extrathyroidal invasion was seen in 68.2% of the tumors harboring both mutations vs. 12.1% of wild-type (P<.001); vascular invasion was seen in 35% of tumors harboring both mutations vs. 14.3% of wild-type (P=.016); lymph node metastases were seen in 60.9% of tumors harboring both mutations vs. 22.3% of wild-type (P<.001); stage III/IV status was seen in 69.6% of tumors harboring both mutations vs. 16.5% of wild-type (P<.001); and recurrence was seen in 60.9% of tumors harboring both mutations vs. 10.3% of wild-type (P<.001).
Xing also showed that tumors with combination of BRAF and TERT mutations were more likely to recur than tumors harboring either mutation by itself. Tumors harboring both mutations showed a recurrence rate of 60.9% vs. 20.4% in BRAF-only tumors (P<.001) and 22.2% in TERT-only tumors (P=.025).
Crude HR calculations put patients with tumor harboring both mutations at a 6.93 HR (95% CI, 3.55-13.53). When adjusted for age at diagnosis, gender, multifocality, tumor size and I-131 treatment, that ratio increased to 8.22 (95% CI, 3.05-22.1). Further adjustment for extrathyroidal invasion, vascular invasion, lymph node metastasis and tumor stage III/IV still resulted in a significant ratio of 4.76 (95% CI, 1.54-14.71).
For more information:
Xing M. Short Call Oral 6. Presented at: the 83rd Annual Meeting of the American Thyroid Association; Oct. 16-20, 2013; San Juan, Puerto Rico.
Disclosure: Xing reports receiving royalties as co-holder of US patent on the BRAF V600E mutation.
Perspective
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R. Michael Tuttle, MD
Currently, the initial therapy, early follow up and long-term follow up of papillary thyroid cancer is very much based on the risk of recurrence and death. Therefore, any new molecular marker that helps us better understand the risk of recurrence and progression has the potential to alter our initial treatments and our follow up recommendations.
As with all molecular markers, it remains to be seen how much the molecular status improves the staging that is based on the clinical findings. For example, most of the TERT/BRAF tumors were stage III or IV, often with invasion and lymph node metastases and, as a consequence, were already classified as high risk tumors. However, some of the cases did not have aggressive clinical features.
Future studies will be needed to determine if these molecular abnormalities in tumors that would have otherwise been classified as low risk convey an increased risk of poor outcomes. Because these molecular analyses are not routinely available in clinical labs, this information will not be immediately implemented into daily practice, but could in the future if these findings are verified in other studies and thought to be clinically useful.
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