Comprehensive survey of HRAS, KRAS, and NRAS mutations in proliferative thyroid lesions from an ethnically diverse...

The distribution and kind of rat sarcoma viral oncogenes homolog (RAS) mutations, as well as their clinical impact on different types of thyroid lesions, vary widely among the different populations studied. We performed a comprehensive mutational survey in the highly related RAS genes HRAS, KRAS, and NRAS in a case series of proliferative thyroid lesions with known BRAF mutational status, originating from an ethnically diverse group.

Mutational hotspot regions encompassing codons 12, 13, and 61 of the RAS genes were directly sequenced in 381 cases of thyroid lesions. In addition, the putative NRAS hotspot region encompassing codon 97 was sequenced in 36 thyroid lesions. The case series included lesions of Hashimoto's thyroiditis (HT), nodular goiters, hyperplastic nodules, follicular adenomas (FAs), Hurthle cell variants of FA, papillary thyroid carcinomas (PTCs), follicular variants of PTC (FVPTCs), microcarcinomas of PTC (micro PTCs; tumor size ≤1 cm), follicular TCs (FTCs), Hurthle cell variants of FTC, and non-well-differentiated TCs (NWDTCs).

We identified RAS mutations in 16 out of 57 (28.1%) FAs, 2 out of 8 (25%) NWDTCs, 8 out of 42 (19.0%) FVPTCs, 2 out of 10 (20.0%) FTCs, 1 out of 12 (8.3%) Hurthle cell variants of FA, 3 out of 46 (6.5%) goiters, 1 out of 18 (5.6%) hyperplastic nodules, 3 out of 56 (5.4%) micro PTCs, 2 out of 115 (1.7%) PTCs, 0 out of 7 (0%) Hurthle cell variants of FTC, and 0 out of 10 (0%) HT lesions. NRAS codon 61 mutation was the predominant form, followed by HRAS codon 61 mutation. Only three mutations affected RAS codons 12 and 13, two of which were identified in goiters. No codon 97 mutation was detected in the examined FVPTCs. An as yet undescribed deletion of KRAS codon 59 was identified in one FA.

RAS mutations in our case series were commonly associated with follicular-patterned thyroid lesions. Our data suggest that FAs with a RAS mutation may constitute precursor lesions for TC with follicular histology. The newly-discovered KRAS codon 59 deletion is one of the first reported codon deletions in a RAS hotspot region.