PDF(Pubmed)
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.
摘要：
迄今为止,在某些甲状腺癌(TC)中强调酪氨酸激酶抑制剂侵袭性和耐药性的分子机制尚不清楚.我们报告了一名年轻患者的转移性低分化（PDTC）和滤泡性甲状腺癌（FTC）对常规疗法和索拉非尼均无效。病人,尽管最初有部分反应，诊断后21个月死于进行性疾病。对原发肿瘤，淋巴结和远处转移瘤进行的遗传分析可以鉴定出移码突变（p。P248Tfs*5）在PTEN基因中，从未在TC中描述过。这种突变存在于原发性肿瘤中，具有较低的等位基因频率，在用索拉非尼治疗后诊断的转移中。TP53中的突变（p。以前在间变性癌中检测到的C135Y和c.920-2A>G，在TC中从未发现p.M133R）也在原代组织中检测到，并在RNA水平上检测到p.C135Y突变体的单等位基因表达。在转移部位水平，我们仅发现TP53剪接突变c.920-2A>G。还评估了错配修复（MMR）蛋白中缺陷的存在和基因组不稳定性。原发性肿瘤显示MMR蛋白的部分表达以及强烈的基因组不稳定性。总之,我们证明了在转移性FTC患者中体细胞PTEN和TP53突变的罕见组合，连同肿瘤异质性和基因组不稳定性的存在，可能与高肿瘤侵袭性和对治疗的抵抗力有关。
