In this study, we performed a time-trend analysis of demographic, clinical, pathologic, and tumor mutational status of patients with papillary thyroid cancer over a fifteen year time period. Our analysis shows that although demographic, clinical and pathologic factors did not change over this time period, the rate of somatic mutations, especially BRAF V600E, increased significantly.
Thyroid cancer is one of the most rapidly increasing cancer diagnoses worldwide. Several investigators have suggested based on cancer registry data that the increase in incidence may be due to diagnostic scrutiny. For example, Davies and Welch analyzed the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2002 and found that the increase in thyroid cancer was predominantly among small (≤ 2cm) papillary thyroid cancers (3
). Kent and associates also found a similar increase in the number of papillary thyroid cancers ≤ 2 cm in size in Ontario, Canada (10
). Therefore, it has been suggested that the increase in thyroid cancer incidence is a result of diagnostic scrutiny and detection of subclinical disease. In contrast, Chen and associates recently evaluated the Surveillance, Epidemiology, and End Results database between 1988 and 2005 and found an increase in incidence rates for all sizes of tumor (1
). They concluded that the increased incidence across all tumor sizes could not solely be due to increased detection. In our study population, we observed no significant difference in demographic, clinical and pathologic factors over a 15 year period. In patients for whom there was tumor tissue available for molecular analysis, the average tumor size was however smaller in Group III as compared to Groups I and II, and the proportion of occult papillary thyroid cancer (<1 cm) was higher.
Family history of thyroid cancer, head and neck irradiation and ionized radiation exposure are well-established risk factors for thyroid cancer. Over the study time period, there has been one significant radiation population exposure as a result of the Chernobyl reactor meltdown, which has been documented to increase the rate of thyroid cancer in children from regions with significant exposure (11
). However, there has been no significant change in these risk factors at a national or international level to explain the marked increase in thyroid cancer incidence seen across different regions and continents (5
). Our patient population has a significant Russian patient population but ethnicity across the three different time periods was similar. In a recent analysis of county specific thyroid cancer registry data in the United States, higher incidence rates were observed in regions within 90 miles of nuclear power reactor plants (12
). At this time it is unclear what the level of radiation exposure is in this situation and whether such level of radiation exposure would increase the risk of thyroid cancer. Higher ionized radiation exposure as a result of the Chernobyl meltdown have been associated with RET/PTC3 rearrangements in children with papillary thyroid cancer but not BRAF V600E mutations (11
Our main objective was to evaluate the rate of molecular changes that have occurred over time. To our knowledge, this is the first study to evaluate mutational status in thyroid tumors over time. Interestingly, there was a striking difference in presence of not only any somatic mutation in Group III as compared to Group I and II, but specifically BRAF V600E mutation (p<0.001 for both). Group III had an overall 92% somatic mutation rate and an 88% BRAF V600E mutation rate, significantly higher than in the other two groups. This increase in somatic mutation rate was independent of clinical and pathologic variables which were similar across the three time periods for the entire cohort as well as for those only for which tumor sample was available, except for tumor size. This would suggest that a rise in BRAF mutation rate may account for the higher incidence of papillary thyroid cancer. It is unlikely that longer period of tumor sample storage or tumor sample quality affected the mutation rates over time as the quality of the nucleic acid extracted was similar across the three time periods, and the thyroglobulin gene copy level was similar across the three time periods. The precise reason for such an increase in BRAF V600E mutation over time is unclear but may reflect increased exposure to chemical carcinogenes or other environmental factors that may make this mutation more prevalent.
One of the limitations of our study is that it was performed in a cohort from a single institution and thus may not be generalizable. However, such an analysis of a cohort from a single institution allows for more detailed analysis of demographic and clinical characteristics in conjunction with the mutation analysis of tumor samples. At the very least our single institution study provides data for future studies to explore this finding as a reason for the increasing incidence of thyroid cancer, especially given both in vitro and in vivo studies of activating BRAF mutation have demonstrated this oncogene is involved in the initiation and progression of papillary thyroid cancer (14
). The presence of BRAF mutations in papillary thyroid cancer have also been associated with more aggressive disease (e.g. higher rates of extrathyroidal invasion and lymph node metastasis) and higher rate of disease recurrence, even in low risk papillary thyroid cancer cases (16
). The higher rate of BRAF V600E mutation observed in Group III is not likely to be due to differences in disease aggressiveness as the extent of disease across all three groups were similar and the subset of tumors analyzed in Group III were also similar to the entire cohort of patients for that time period ( and ). Another possible weakness in our study is risk factors such as radiation exposure and family history could not be determined in the study population which thus may influence the mutation rate detected. However, radiation exposure is not likely to affect the BRAF V600E mutation rate. And while the association of radiation exposure and RET/PTC3 rearrangements is strong this mutation was observed at a relatively low rate and was not different over time (11
). Lastly, we recognize that an increase in the rate of BRAF mutation during a time in which the incidence of thyroid cancer has doubled does not necessary demonstrate a cause and effect but provides data that should be explored in future studies to understand the factors associated with the increasing incidence of thyroid cancer.
In conclusion, we found higher rates of BRAF V600E mutation over a 15 year period. Our findings suggest a higher rate of somatic mutations in papillary thyroid cancer thus may contribute to the increasing incidence of papillary thyroid cancer. The reason for the increased rate of somatic mutations will need to be evaluated in future studies.