Coexisting BRAF/TERT Mutations Predict Aggressive Thyroid Cancer

Umamaheswar Duvvuri, MD, PhD

Coexisting mutations in BRAF and TERT may be associated with an aggressive phenotype and higher recurrence rates for patients with locally advanced well-differentiated thyroid cancers, according to findings presented at the 2015 International Thyroid Congress.

"These advanced thyroid cancers seem to have a high percentage of multiple mutations," lead investigator Umamaheswar Duvvuri, MD, PhD, assistant professor of otolaryngology specializing in head and neck surgery at the University of Pittsburgh School of Medicine, told OncLive. "Most thyroid cancers have a mutation in the gene BRAF, which is very common; however, most thyroid cancers, small ones at least, tend to only have one mutation, whereas these advanced ones have multiple mutations, most commonly BRAF^V600E and TERT. We think these genes corroborate to allow bad thyroid cancers to form."

In recent years, the incidence of well-differentiated thyroid cancers has increased at an alarming rate, with a near doubling of incidence over the past 6 years, Duvvuri highlighted. As a result, researchers sought to uncover the distinct molecular profiles that could be used as prognostic indicators of future aggressiveness using next-generation sequencing (NGS).

For the study, researchers at the University of Pittsburgh put together a series of mutational panels focusing on the major signal-transducing players controlling papillary thyroid carcinoma oncogenes. This started with a 7-gene panel in 2007, followed by a 15-gene panel by 2013, and then a 56-gene panel in 2014 that employs NGS. Through this process, over 95% of thyroid cancer alterations have been identified, according to Duvvuri.

For the study, researchers selected a group of T4 well-differentiated thyroid cancers that did not have any anaplastic or poorly differentiated areas. All patients were treated with curative intent. Molecular testing was conducted using the ThyroSeq v2.1 panel, which explores 14 point mutations, 42 gene fusions, and 7 cell composition genes.

Overall, 25 samples were procured, processed, and analyzed from patients at a mean age of 58 years (range, 29-86) with well-differentiated T4 thyroid carcinomas. Findings from these samples were compared with a control group of 102 patients with T1-3 well-differentiated thyroid tumors.

In the advanced group, 76% had BRAF mutations, followed most commonly by TERT alterations (56%). Only one patient out of 25 had no identifiable mutation, suggesting that most of the pertinent mutations were currently identifiable, since alterations were detected in 96% of patients. In the control group, a total of 45 patients had BRAF mutations followed by 17 with NRAS, 9 HRAS, 8 KRAS, 1 PTEN, and 8 TERT mutations.

Nearly 48% of the patients with T4 tumors had coexisting mutations in BRAF and TERT. In contrast, in the control group, the rate of coexisting BRAF/TERT alterations was just 5% (P <.001). In the advanced cohort, coexisting mutations in BRAF/TERT were associated with an increased risk of recurrence when compared to tumors without both alterations. Overall, 58.3% of those with both alterations had a recurrence compared with just 18.3% with a separate BRAF or TERT alteration alone (P = .04).

While others have shown that BRAF^V600E mutations are associated with more aggressive cancers, the most aggressive thyroid cancers tend to have multiple mutations. These findings may indicate that comutation in TERT/BRAF are more distinct in advanced thyroid cancer, Duvvuri pointed out.

Duvvuri U, Grimes M, Mady L, et al. Multi-gene next generation sequencing (thyroseq) assay on locally invasive T4 well differentiated thyroid cancer. Presented at: International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 461.

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