Molecular alterations in Hürthle cell nodules and preoperative cancer risk.

Hürthle cell carcinoma (HCC) is a distinct type of thyroid cancer genetically characterized by DNA copy number alterations (CNA), typically of genome haploidization type (GH-type). However, whether CNA also occurs in benign Hürthle cell adenomas (HCA) or Hürthle cell hyperplastic nodules (HCHN), and have diagnostic impact in fine-needle aspiration (FNA) samples, remains unknown. To address these questions, we (1) analyzed 26 HCC, 24 HCA, and 8 HCHN tissues for CNA and other mutations using ThyroSeq v3 (TSv3) next-generation sequencing panel, and (2) determined cancer rate in 111 FNA samples with CNA and known surgical outcome. We identified CNA, more often of the GH-type, in 81% of HCC and in 38% HCA, but not in HCHN. Among four HCC with distant metastasis, all had CNA and three TERT mutations. Overall, positive TSv3 results were obtained in 24 (92%) HCC, including all with ATA high risk of recurrence or metastasis. Among 111 FNA cases with CNA, 38 (34%) were malignant and 73 (66%) benign. A significant correlation between cancer rate and nodule size was observed, particularly among cases with GH-type CNA, where every additional centimeter of nodule size increased the malignancy odds by 1.9 (95% CI 1.3-2.7; P = 0.001). In summary, the results of this study demonstrate that CNA characteristic of HCC also occur in HCA, although with lower frequency, and probability of cancer in nodules with CNA increases with nodule size. Detection of CNA, in conjunction with other mutations and nodule size, is helpful in predicting malignancy in thyroid nodules.

Genetic variation in HIF signaling underlies quantitative variation in physiological and life-history traits within lowland butterfly populations.

Oxygen conductance to the tissues determines aerobic metabolic performance in most eukaryotes but has cost/benefit tradeoffs. Here we examine in lowland populations of a butterfly a genetic polymorphism affecting oxygen conductance via the hypoxia-inducible factor (HIF) pathway, which senses intracellular oxygen and controls the development of oxygen delivery networks. Genetically distinct clades of Glanville fritillary (Melitaea cinxia) across a continental scale maintain, at intermediate frequencies, alleles in a metabolic enzyme (succinate dehydrogenase, SDH) that regulates HIF-1α. One Sdhd allele was associated with reduced SDH activity rate, twofold greater cross-sectional area of tracheoles in flight muscle, and better flight performance. Butterflies with less tracheal development had greater post-flight hypoxia signaling, swollen & disrupted mitochondria, and accelerated aging of flight metabolic performance. Allelic associations with metabolic and aging phenotypes were replicated in samples from different clades. Experimentally elevated succinate in pupae increased the abundance of HIF-1α and expression of genes responsive to HIF activation, including tracheal morphogenesis genes. These results indicate that the hypoxia inducible pathway, even in lowland populations, can be an important axis for genetic variation underlying intraspecific differences in oxygen delivery, physiological performance, and life history.