High Prevalence of RET, RAS, and ERK Expression in Hashimoto's Thyroiditis and in Papillary Thyroid Carcinoma in the Korean Population

Abstract

The RET/PTC-RAS-BRAF cascade is associated with papillary thyroid carcinoma (PTC). The relationship between PTC and Hashimoto's thyroiditis (HT) is still elusive. To determine whether thyrocytes showing oxyphil cell metaplasia in HT also express RET, RAS, and ERK proteins, which are associated with PTC. We investigated the expression of RET, RAS, and ERK proteins in oxyphil cells in the vicinity of large lymphoid HT infiltrates and in malignant PTC cells. BRAF and N-RAS missense mutations were also examined in oxyphil cells of the HT. We used 47 PTC samples with no HT diagnosis, 28 PTC with HT, 39 HT with no PTC, and 36 HT with PTC. We also studied 75 normal portions of thyroid tissue from PTC specimens. Immunohistochemical analysis and polymerase chain reaction were used to determine activation of the RET/PTC-RAS-BRAF cascade in HT and PTC. In PTC cells, HT oxyphil cells, and normal thyrocytes, the frequency of high RET expression was 23/70 (32.9%), 36/57 (63.2%), and 1/57 (1.8%) (p = 0.000); that of high nuclear localized RAS expression (nuclearRAS) was 65/71 (91.5%), 52/58 (89.7%), and 5/58 (8.6%) (p = 0.000); and that of high ERK expression was 38/70 (54.3%), 34/61 (55.7%), and 0/61 (0.0%) (p = 0.000), respectively. Of 66 HT cases studied for BRAF mutation and 57 HT cases studied for N-RAS mutation, no BRAF exon 15 or N-RAS exon 2 mutations were found in the amplified DNA extracted from oxyphil cells excised by laser capture microdissection. The expression of RET, nuclearRAS, and ERK proteins is greatly enhanced in PTC cells and HT oxyphil cells. Thus, the RET/PTC-RAS-BRAF cascade may be involved in the development of PTC and oxyphil cell metaplasia in HT. Our results show the possibility of a molecular link between oxyphil cell metaplasia in HT and the progression of PTC.