Thyroid cancer harboring PTEN and TP53 mutations: A peculiar molecular and clinical case report

Abstract

To date, the molecular mechanisms that underline aggressiveness and resistance to tyrosine kinase inhibitors in some thyroid carcinomas (TCs) are not known yet. We report the case of a young patient with a metastatic poorly differentiated (PDTC) and follicular thyroid carcinoma (FTC) refractory to conventional therapies and to Sorafenib. The patient, despite an initial partial response, died of progressive disease 21 months after diagnosis. The genetic analysis performed on the primary tumor and on lymph nodes and distant metastases allowed to identify a frameshift mutation (p.P248Tfs*5) in the PTEN gene, never described in TC. This mutation was present in the primary tumor and, with a lower allelic frequency, in metastases diagnosed after treatment with Sorafenib. Mutations in TP53 (p.C135Y and c.920-2A>G previously detected in anaplastic carcinomas and p.M133R never found in TC) were also detected in the primary tissue together with a mono-allelic expression of the p.C135Y mutant at RNA level. At metastatic sites level, we found only the TP53 splicing mutation c.920-2A>G. The presence of defects in mismatch repair (MMR) proteins and genomic instability was also evaluated. The primary tumor showed a partial expression of MMR proteins together with a strong genomic instability. In conclusion, we demonstrated that the rare combination of somatic PTEN and TP53 mutations in a patient with a metastatic FTC, together with the presence of tumor heterogeneity and genomic instability, might be associated with a high tumor aggressiveness and resistance to treatments.

Drug repositioning in thyroid cancer: from point mutations to gene fusions

“…In this scenario, it is worth looking at how alpelisib can counteract the resistance mechanism by diminishing the EPH receptor B2 ( EPHB2 )-induced signaling ( 38 ). Consistent with the latest, PTEN , which has a negative regulatory role in the same pathway, has reported variants in TC ( 39 ).…”

Oxidative Stress Correlates with More Aggressive Features in Thyroid Cancer

“…RNA was reverse-transcribed (Reverse Transcription System, Promega, Madison, WI, USA) and three different assays were used to interrogate 15 point-mutations in 8 genes (BRAF, H-RAS, N-RAS, K-RAS, EIF1AX, AKT1, PIK3CA, TERT) in DNA and 7 gene fusions (RET-PTC1, 2 and 3, TRK, TRKT1, and T3 and PAX8-PPARγ) in cDNA. The molecular analysis of TP53 (exons 2–11) and PTEN (exons 5–8) was performed by PCR amplification and direct sequencing [ 28 ].…”

Autophagy-Related MicroRNA: Tumor miR-125b and Thyroid Cancers

“…PRDM1 is a key target in Hashimoto thyroiditis [ 79 ]. TP53 is an oncosuppressor associated with metastatic PTC [ 80 ].…”

“…The association of hsa-mir-125b with STAT3, PRDM1, TP53, EZH2, NFkB1, AKT1, ERS1 and PPARG was revealed. The complex of factors represented the processes activated in PTC development [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. They recover the mechanism of immune response, microenvironment modification, hormone receptors signal transduction, oxidative stress and etc.…”