Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines.

Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.

Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling.

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.

Iron status and developmental scores in 6-year-olds highlights ongoing need to tackle iron deficiency in infants.

AIM: To investigate iron status and developmental scores at 6 years of age in a population with decreased prevalence of iron deficiency in infancy. Iron status at 6 years and tracking from 12 months were also studied. METHODS: Children (n = 143) born in Iceland in 2005 were followed up at the age of six. Motor and verbal development was assessed by a parental questionnaire, and iron status was assessed by Hb, MCV and serum ferritin (SF). Iron depletion was defined as SF <15 µg/L and deficiency as MCV <76 fL and SF <15 µg/L. RESULTS: Iron depletion was observed in 5.6% of 6-year-olds, and 1.4% were iron deficient. Self-help (subset in motor development) differed by -4.14 (95% CI = -7.61, -0.67), between those iron depleted at 12 months (n = 6) and those nondepleted (n = 102), adjusted for maternal education. The combined motor developmental score seemed lower in iron depleted infants, although of borderline significance (p = 0.066). MCV concentration tracked from 12 months to 6 years (r = 0.31, p < 0.002), but Hb and SF did not. CONCLUSION: Improved iron status at 12 months and 6 years has diminished the public health threat associated with iron depletion in the population studied, but iron depletion and development still associate weakly. Action to prevent iron depletion in infancy remains important.