Next-Generation Sequencing Suggests BRAF With TERT Comutation Occurs in Advanced Well-differentiated Thyroid Cancer

Researchers have posited that well-differentiated thyroid cancers harbor distinct molecular pathological profiles that may be useful as prognostic indicators of future aggressiveness.

Umamaheswar Duvvuri, MD, PhD

Researchers at the University of Pittsburgh have been working with the hypothesis that well-differentiated thyroid cancers harbor distinct molecular pathological profiles that may be useful as prognostic indicators of future aggressiveness.

Umamaheswar Duvvuri, MD, PhD, assistant professor of otolaryngology specializing in head and neck surgery at the University of Pittsburgh School of Medicine, presented work describing next-generation sequencing (NGS) of locally advanced, well differentiated thyroid cancers (WDTCs) during a session at the 15th International Thyroid Congress. Duvvuri highlighted that the incidence of WDTCs has increased at an alarming rate, and he presented data showing a near doubling of incidence over the past 6 years.

The University of Pittsburgh has 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, which led to a 15-gene panel by 2013, and then a 56-gene panel in 2014 that employs NGS. Through this process, they have gone from identifying mutations in 70% of the tumors to identifying mutations in over 95% of the tumors, according to Duvvuri. The researchers used various markers including pan-thyroid markers to ensure that they are looking at the correct tissues for their molecular analysis.

While others have shown thatBRAF600Emutations are associated with more aggressive cancers, Duvvuri et al have observed that the most aggressive thyroid cancers tend to have multiple mutations including mutations inTP53. To study this finding, they identified a group of T4 WDTCs that did not have any anaplastic or poorly differentiated areas. All patients were treated with curative intent.

Starting with 80 patients with DTC, the researchers excluded those with tumors that were not well differentiated and those for which insufficient tissue could be harvested. They procured, processed, and analyzed 25 samples from well-differentiated T4 thyroid carcinomas. The mean age was 58 years (29-86), and patients were followed for 5 years. A total of 85% hadBRAFmutations, followed most commonly by theTERTmutation. Only one patient out of 25 had no identifiable mutation, suggesting that most of the pertinent mutations were currently identifiable because 96% (24/25) of patients were identified.

Most interestingly, 50% of the patients had mutations in bothBRAFandTERT; however, only 4% of T1-3 tumors (5/103) demonstratedTERT/BRAFV600Ecomutations. Therefore, the researchers evaluated a control cohort that looked at 102 patients with early-stage cancer. A total of 45 patients hadBRAFmutations followed by 17NRAS, 9HRAS, 8KRAS, 1PTEN, and 8TERTmutations. Of these 8TERTmutations, only 5 had comutations inBRAF. Duvvuri pointed out that this means 5% of early mutations have theBRAFwithTERTcomutation, while advanced cancers have 50%BRAFwithTERTcomutation, which may indicate that this comutation is more distinct in advanced thyroid cancer.

Next Duvvuri et al looked at the impact of these mutations on the likelihood for recurrence or death. They observed a roughly three-fold increase in the recurrence of T4 WDTCs in patients that possessed theBRAFwithTERTcomutation.

Duvvuri et al have found that advanced well-differentiated thyroid cancers do tend to have a characteristic molecular profile, which includes a high rate of BRAF withTERTcomutations, and these subtypes have a higher recurrence rate. Most advanced WDTCs have a high rate of mutation with a particularly high rate ofBRAFwithTERTcomutation. The University of Pittsburgh group is actively investigating how well this comutation correlates with the more aggressive phenotype.

Duvvuri U. Multi-gene next generation sequencing (thyroseq) assay on locally invasive T4 well differentiated thyroid cancer. Presented at the 15th International Thyroid Congress: Lake Buena Vista, Florida; October 21, 2015. Abstract #461.