The Presence of Combined BRAF, TP53 and PIK3CA Mutations Have Prognostic Impact in the Hobnail Variant of Papillary Thyroid Carcinoma

Background: Hobnail variant of papillary carcinoma (HPTC) represents a recently described aggressive and rare group of moderately differentiated thyroid tumors with poorly understood pathogenesis. Molecular data in this group of tumors are heterogeneous, possibly reflecting the rarity of this entity, and there is the need for a more detailed molecular characterization of these tumors. The objective of the study was to define a comprehensive molecular typing of HPTC. Design: Twelve cases of HPTC, including eight primary tumors and four lymph node metastases, from eight patients selected through the files of University of Turin, Italy, have been screened for N-K-H-RAS, BRAF, TP53, PIK3CA and NOTCH1 gene mutations generating locus-specific amplicon libraries with tagged primers for the above genes. Sequencing was conducted on the Roche/454 GS junior system and quality-filtered reads were analyzed with the GS Amplicon Variant Analyzer (AVA 2.7, 454 Life Sciences). Molecular data were compared with clinical-pathologic data and follow up. Results: The patients included 5 women and 3 men. Ages ranged from 31 to 87 years. All twelve cases of HPTC showed more than 30% hobnail features. BRAF and HRAS mutations were by far the most common genetic alterations in HPTC (41.7% and 33.3% respectively). V600E BRAF mutation was detected both in primary and metastasis in two patients and in one primary tumor in one patient. TP53 deleterious mutations were found in two primary HPTC and in one metastasis. PIK3CA gene mutations was found in 3 cases and KRAS in one case. No mutation was detected in the NRAS and NOTCH1 genes. Interestingly, only the three patients (37.5%) who died of disease after a mean of 30.6 months, showed the same complex molecular characterization constituted by the presence of combined mutations. Conclusions: The present study confirms that HPTC are genetically heterogeneous and complex. The presence of combined mutations in BRAF, TP53 and PIK3CA genes appear to have a negative prognostic factor. The detection of these multiple mutations by molecular profiling should be clinically relevant for the prognostic stratification and treatment of these patients.