Genetic differences in follicular thyroid carcinoma between Asian and Western countries: a systematic review

Thyroid cancer is the most common endocrine malignancy, and follicular thyroid carcinoma (FTC) is the second most common thyroid cancer following papillary thyroid carcinoma (PTC). RAS mutation and PAX8/PPARγ rearrangement are the two representative genetic alterations in FTC, and there are studies from various countries on their regional frequencies. In this study, we systematically reviewed all available literature aiming to create a complete global map showing the frequencies of these common oncogenic drivers in FTC and to highlight the trends in Asian and Western countries. We performed a search in two electronic databases and identified 71 studies that fit our criteria from 1,329 studies found with our database search terms. There were 54 articles with 1,143 FTC patients and 39 articles with 764 FTC patients available for calculating the frequency of RAS mutation and PAX8/PPARγ rearrangement, respectively. NRAS mutation was the most frequent RAS mutation in all regions, followed by HRAS and KRAS mutation. The frequency of RAS mutation in Asian countries was higher than Western countries (34% vs. 27%, P=0.006) when the mutation detection method was not taken into account. In contrast, this difference in RAS mutation incidence between Asian and Western countries (28% vs. 25%, P=0.47) did not show up in our subgroup analysis incorporating only studies using direct sequencing method. The reported difference of RAS mutation frequency in the previous literature might not be due to the true prevalence of RAS mutation. They could be attributed to the difference in the detection method. As to PAX8/PPARγ rearrangement, Western countries overall had a much higher prevalence than Asian countries (23% vs. 4%, P<0.001), but some European countries had a low incidence, implying regional heterogeneity of PAX8/PPARγ rearrangement. A substantial lack of mutation data in FTC was found in several regions of the world such as Central Asia, Middle East, Africa, and Central and South America. Our results provide the most comprehensive global status of representative genetic alterations in FTC and highlight the similarities and differences between Asian and Western countries.