Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer

Abstract

Background Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. Methods Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. Results The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. Conclusions This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis

“…Meanwhile, loss of function nonsense mutation in TP53 (i.e., TP53 R342* ) arise together with CDK4 R24C , with the same trend of increased content from lyn 3 to BM ( Figure 2D ), indicating they are mutated in the same subclone. The important roles of TP53 on tumor have been well-established, and a series of studied (e.g., TCGA project) also indicated the rare TP53 mutation rate in PTC (<1%) compared to ATC (>30%) ( 45 , 46 ), and contribution of TP53 loss to the dedifferentiation of differential thyroid cancer ( 15 , 47 , 48 ), which is also experimentally validated in our study. Indeed, mutation frequency of different types of thyroid cancer varied in parallel with their differentiated states, with the highest TP53 mutation rate observed in ATC (the poorest differentiated subtype of thyroid cancer), while lowest in cPTC (the most differentiated subtype) ( 12 , 44 ), further supporting the contribution of TP53 deficiency to dedifferentiation of thyroid cancer.…”

Characterizing dedifferentiation of thyroid cancer by integrated analysis

“…In addition, 17 of 28 available formalin-fixed, paraffin-embedded samples from patients with ATC were positively stained with CREB3L1, independently of common somatic mutations in driver genes (i.e., TP53, BRAF , and TERT ) (fig. S7B) ( 10 ).…”

“…This fluctuation may involve varied genetic alterations in different cancer types. For thyroid cancer, although BRAF V600E mutation frequently occurred in both ATC and PTC, common mutations in TP53 and the TERT promoter that present in ATC are rare in PTC (8)(9)(10)(11). It suggests that the accumulation of genetic alterations may facilitate PTC to dedifferentiate into ATC by influencing cellular plasticity.…”

The Impact of Recent Developments in Electrochemical POC Sensor for Blood Sugar Care

“…The glucose sensor consists of a modified electrode that selectively catalyzes the oxidation of glucose on the electrode surface and a transducer that converts the chemical signal of the reaction into an electrical signal that is displayed by an instrument ( Zhang et al, 2021 ). Various types of glucose sensors can be constructed by applying different modified electrodes.…”