Somatic mutation profiling of hobnail variant of papillary thyroid carcinoma

Abstract

Hobnail variant of papillary thyroid carcinoma (HPTC) represents a recently described, aggressive and rare group of thyroid tumors with poorly understood pathogenesis. Molecular data about this group of cancers are few, and a more detailed molecular characterization of these tumors is needed. The main objective of the study is to define a comprehensive molecular typing of HPTC. Eighteen patients affected by HPTC, including eighteen primary tumors and four lymph node metastases, were screened forNRAS,KRAS,HRAS,BRAF,TP53,PIK3CA,hTERT,PTEN,CDKN2A,EGFR,AKT1,CTNNB1andNOTCH1gene mutations. Sequencing is conducted on the MiSEQ system, and molecular data are compared with clinical-pathologic data and follow-up. The patients include 14 women and 4 men. Ages range from 23 to 87 years. All 18 primary tumors of HPTC showed ≥30% hobnail features.BRAFandTP53mutations are by far the most common genetic alterations in primary HPTC (72.2% and 55.6%, respectively), followed byhTERT(44.4%),PIK3CA(27.8%),CTNNB1(16.7%),EGFR(11.1%),AKT1(5.5%) andNOTCH1(5.5%). The mutational pattern in primary tumors and metastasis was usually maintained. Univariate Cox regression analyses with bootstrap procedure indicated a significantly increased mortality risk in patients harboringBRAFmutation andBRAFmutation associated withTP53and/orPIK3CAmutations. The detection of these multiple mutations appears to allow the identification of a subset of more aggressive tumors within the group and to bear information that should be useful for prognostic stratification of these patients including the planning of adjuvant therapy.