Has the Genetic Profile of Papillary Thyroid Cancer Changed?

Kenneth D. Burman, MD


September 20, 2012

Modifications in the Papillary Thyroid Cancer Gene Profile Over the Last 15 Years

Romei C, Fugazzola L, Puxeddu E, et al
J Clin Endocrinol Metab. 2012; 97: E1758-E1765

Article Summary

Thyroid cancer has been increasing in frequency at an alarming rate.[1] It is now recognized that a somatic BRAF mutation (V600E) in papillary thyroid cancer tissue occurs in about 40%-60% of papillary thyroid cancer cases and a RET/PTC rearrangement occurs in approximately 40% of them.[2,3,4,5,6,7,8] There is wide variability in the reported frequency of occurrence of these mutations, probably related to geographic variation, history of radiation exposure, and technical differences.[9]

BRAF mutations are associated with an increased risk for cervical lymph node metastasis and increased disease progression and recurrence.[2,10] RET/PTC3 rearrangements may be associated with more aggressive activity and large tumor size.[11,12,13] However, there are 3 isoforms of RET/PTC, and it is thought that when all isoforms are considered together, patients with RET/PTC rearrangements may present at a younger age with classic papillary thyroid histology and may have a more favorable prognosis.[9,10,11,12,13,14]

An important unanswered question relates to the mechanism of the rapid increase in papillary thyroid cancer cases. It is actively debated whether the increased frequency of papillary thyroid cancer is related simply to improved detection, or whether a change in the basic nature of thyroid cancer has occurred.[1]

The study by Romei and colleagues was conducted in Italy. The investigators analyzed 401 patients with papillary thyroid cancer and divided these patients into 3 categories based on the period of diagnosis. Clinical, pathologic, and molecular features were analyzed in these 401 patients; molecular characteristics were studied in an additional 459 patients from Sicily who had papillary thyroid cancer.

Remarkably, the incidence of BRAF mutations increased from 28% in 1996-2000, to 48.9% in 2001-2005 and 58.1% in 2006-2010. The frequency of RET/PTC rearrangements, in contrast, decreased from 33% in 1996-2000 to 17% in 2001-2005 and 9.8% in 2006-2010. Furthermore, the mean age at diagnosis of papillary thyroid cancer increased over time, and the mean thyroid cancer tumor size decreased. There were more patients with stage 1 disease in the more recent time groups, but there were no apparent changes over time regarding the percentage of patients with cervical node metastasis or distant metastases, and there were no changes in the percentage of patients with the classic variant of papillary thyroid cancer.

In the subgroup of patients from Sicily, a similar statistically significant increase (P < .001) in BRAF mutations was observed, but only 2 of the 459 patients had RET/PTC rearrangements.

The investigators speculate that the increasing age at diagnosis of papillary thyroid cancer may relate to the increasing frequency of BRAF mutations and the overall decreasing frequency of RET/PTC mutations. They also wonder whether environmental exposure, such as pollutants or radiation, may contribute to these changes.


The article by Romei and colleagues has addressed an important question regarding the increasing incidence and aggressiveness of differentiated thyroid cancer. They found an impressive increase in frequency of somatic BRAF mutations from 1995 to 2010 and, conversely, a decrease in the frequency of somatic RET/PTC rearrangements. The underlying mechanisms for these genetic changes are unknown. The investigators speculate that they could be related to increasing age at diagnosis or environmental changes (such as radiation exposure from the Chernobyl nuclear accident).

There is little doubt, however, that differentiated thyroid cancer has increased in frequency over the past several decades.[1] Using the Surveillance, Epidemiology, and End Results (SEER) thyroid cancer database, Davies and Welch[1] noted a 2.9-fold increase in papillary thyroid cancer from 2.7 to 7.7 per 100,000 persons over the approximately 30-year period from 1973 to 2002. The majority of these papillary thyroid cancers were small in size (87% were 2 cm or smaller). They speculate that this increase is probably related to enhanced detection of tumors, rather than an actual increase in incidence.[1] Chen and colleagues[15] confirmed this increase and noted a particular rise in women aged 45 years or older, with a lesser rise in men aged 45 years or older.

Although overall mortality remained relatively similar over this period, the rates of distant metastases in men increased from 4% to 9%, and the annual percentage change in thyroid cancer mortality in men increased by 2.4% -- the largest increase of any type of thyroid cancer.[1,16] These observations suggest that the increase in differentiated thyroid cancer is related in large part to increased detection, but given the increases in distant metastases and mortality in men, there must also have been changes in the basic nature of some of the tumors.

Although the basic mechanisms that cause and mediate the genesis and propagation of differentiated thyroid cancer are largely unknown, advances have been made in elucidating the basic pathways that are important.[17,18,19] BRAF mutations (V600E) are the most common somatic thyroid cancers, with a smaller number of RET/PTC or RAS mutations also being noted.[19,20] These mutations occur in a mutually exclusive manner, and in total, about 70%-90% of papillary thyroid cancer tissue will exhibit one of these mutations.

The study by Romei and colleagues provides useful information regarding the potential mechanisms by which papillary thyroid cancer has increased in incidence over the past 3 decades. There clearly has been a modification in the somatic genetic profiles in papillary thyroid cancer, with an increase in frequency of BRAF mutations and a concomitant decrease in RET/PTC mutations. It appears that BRAF mutations are associated with more aggressive tumor characteristics, thus perhaps explaining a portion of the increased papillary thyroid cancer incidence and mortality.[2,10]

However, controversy has arisen about the unique relationship between BRAF mutations and the aggressiveness of thyroid cancer. The BRAF mutation occurs in about 40%-60% of cases of papillary thyroid cancer, and as noted, it is associated with an increased risk for aggressive behavior. However, only about 5%-10% of papillary thyroid cancers are considered highly aggressive.

This discordance has been put into perspective by 2 recent studies by Guerra and colleagues[2,21] and in an editorial by Xing.[10] There is heterogeneity of BRAF expression within a given nodule, and there may also be a second mutation (eg, RAS) within the nodule, but in separate cells.

Furthermore, a newer technique, pyrosequencing, allows quantitative assessment of BRAF mutations.[2] If more than 25% of alleles contain the BRAF mutation, the tumor is more likely to be aggressive. Thus, it is not simply the presence or absence of a BRAF mutation, but its frequency in a given nodule, that may be important.

Xing[10] also discusses whether a BRAF or RET/PTC mutation is a primary or secondary event in tumor genesis and propagation. This issue has not been resolved, as there is evidence on both sides. Heterogeneity of mutant BRAF alleles with the majority of alleles in a thyroid nodule harboring wild-type BRAF alleles, and the presence of cells containing mutant BRAF alleles and separate cells in the same thyroid nodule harboring RAS mutant alleles, suggest that BRAF mutation may be a secondary event in the genesis of thyroid cancer.[10] On the other hand, BRAF is related to tumor aggressiveness, and in animal studies, it clearly can initiate tumor development and progression.[10,22]

Further understanding whether a molecular event (eg, BRAF mutation) is primary or secondary, and elucidation of primary and secondary molecular pathways, will aid in the development of agents that can be used clinically and in the improved recognition and diagnosis of thyroid cancers that may exhibit aggressive behavior. At present, however, we don't know who wakes the bugler.[23]