Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies RAS and PIK3CA Mutations as Negative Survival Predictors

Abstract

Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive. We investigated the association of selected driver mutations, including BRAF, RAS, PIK3CA, TERT promoter, TP53, POLE, and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic and predictive biomarkers. Thirty-nine retrospective cases from pathology archives were enrolled for clinicopathology analysis and immunohistochemistry, and 27 cases had sufficient specimens for further molecular testing using targeted next-generation sequencing and mass spectrometry. BRAFV600E and RAS mutations were identified in 25.9% and 40.7% of ATC, respectively. BRAFV600E mutation was significantly associated with coexisting papillary thyroid carcinoma (p = 0.009) and RAS mutations with female gender (p = 0.012). In univariant analysis, the non-BRAF/RAS tumors were significantly associated with the presence of a sarcomatoid pattern (p = 0.045). PIK3CA, TERT promoter, and TP53 mutations were identified in 14.8%, 81.5%, and 70.4% of cases, respectively. No MMR-D or POLE mutations were detected. In survival analyses, RAS and PIK3CA mutations were significantly associated with inferior outcomes (p = 0.03 and p = 0.006, respectively). In conclusion, driver mutations in ATC are associated with distinct clinicopathological features. RAS and PIK3CA mutations were negative predictors for patient survival. Emerging therapeutic agents targeting BRAF, RAS, and PI3 kinase may benefit a substantial proportion of ATC patients.

The prevalence of DNA microsatellite instability in anaplastic thyroid carcinoma – systematic review and discussion of current therapeutic options

“…For only 1 case, an associated well-differentiated tumour component was reported [ 14 ]. Three of the studies did not detect MSI cases [ 25 – 27 ].…”

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells

“…ATC remains a clinical challenge due to its highly aggressive characteristics [ 1 , 3 , 4 ]. The most common driver mutations for anaplastic thyroid cancer occur in the BRAF or RAS genes, and drugs that target the BRAF kinase have had higher response rates than cytotoxic chemotherapy [ 20 ]. Targeted therapy appears promising against ATC; however, only 20–40% of ATCs harbor a BRAF mutation [ 21 ].…”

Neuerungen in der Systemtherapie des Anaplastischen Schilddrüsenkarzinoms

“…Die Frequenz von BRAF-und RAS-Mutationen schwankt je nach Sequenziermethode, regionaler Herkunft der Tumorsamples und der zugrunde liegenden Klassifikation (Turin-Klassifikation, MSKCC-Kriterien) deutlich. BRAF-V600E-Mutationen sind mit einem kleineren Tumordurchmesser und vermehrten Lymphknotenmetastasen assoziiert und treten gehäuft in Kombination mit einem gleichzeitig bestehenden papillären Schilddrüsenkarzinom auf [17]. Eine zusätzliche p53-Mutation (54-64 %) und/ oder TERT-Mutation (61 %) markiert oft den Übergang vom PTC in ein ATC.…”

“…Eine zusätzliche p53-Mutation (54-64 %) und/ oder TERT-Mutation (61 %) markiert oft den Übergang vom PTC in ein ATC. RASmutierte Tumoren sind häufig größer, weisen mehr Fernmetastasen auf und sind mit einer schlechteren Prognose assoziiert [17]. Tumoren, die zusätzlich zu einer RAS-Mutation eine EIF1AX-Mutation aufweisen (9 % der ATC), zeigen eine noch höhere Proliferation und ein kürzeres Überleben.…”