Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H^M1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (Ca_V3.2) expressed in adrenal glomerulosa. CACNA1H^M1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca²⁺, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

The fifth edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization. This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed as ‘thyroid follicular nodular disease’ to better reflect the clonal and non-clonal proliferations that clinically present as multinodular goiter. Thyroid neoplasms originating from follicular cells are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered a distinct malignant thyroid neoplasm of uncertain histogenesis. The ‘differentiated high-grade thyroid carcinoma’ is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised fifth edition of the WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.