Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1.
Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1.
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DOI：
10.1158/0008-5472.can-09-0727
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Fagin JA
中科院分区：
文献类型：
--
作者：
Ricarte-Filho JC;Ryder M;Chitale DA;Rivera M;Heguy A;Ladanyi M;Janakiraman M;Solit D;Knauf JA;Tuttle RM;Ghossein RA;Fagin JA
低分化 (PDTC)、间变性 (ATC) 和放射性碘难治性 (RAIR) 分化型甲状腺癌患者死亡率较高，特别是 18F-氟脱氧葡萄糖正电子发射断层扫描 (FDG-PET) 呈阳性时。为了获得晚期甲状腺癌的全面遗传信息，我们设计了一个质谱基因分型检测组，涵盖了该疾病中最重要的癌基因：在31个细胞系、52个原发肿瘤（34个PDTC和18个ATC）和55个RAIR、FDG-PET阳性中调查了RET、BRAF、NRAS、HRAS、KRAS、PIK3CA、AKT1和其他相关基因的111个突变42 名患者的复发和转移（淋巴结和远处）。在原发性 PDTC 中，RAS 突变比 BRAF 更常见（44% vs 12%；p=0.002），而在 PET 阳性转移性 PDTC 中，BRAF 比 RAS 更常见（39% vs 13%，p=0.04）。 BRAF 突变在 ATC (44%) 和 RAIR PTC 患者的转移性肿瘤 (95%) 中非常普遍。在多发转移的患者中，9/10 的患者表现出 BRAF 或 RAS 突变的样本间一致性。相比之下，5/6 的患者 PIK3CA 或 AKT1 突变不一致。在 10 个标本中发现了 AKT1_G49A，仅在转移瘤中。这是甲状腺癌中 AKT1 突变的第一份文献。因此，RAIR FDG-PET 阳性转移瘤富含 BRAF 突变。如果原发灶中 BRAF 发生突变，转移灶很可能会存在缺陷。相比之下，一个样本中不存在 PIK3CA/AKT1 突变可能无法反映其他位点的状态，因为这些突变是在进展过程中出现的，这是针对 PI3K 效应器的治疗的一个重要考虑因素。
Patients with poorly differentiated (PDTC), anaplastic (ATC) and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTCs and 18 ATCs) and 55 RAIR, FDG-PET positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 vs 12%; p=0.002) in primary PDTC, whereas BRAF was more common than RAS (39 vs 13%, p=0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9/10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5/6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 10 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites since these mutations arise during progression, an important consideration for therapies directed at PI3K effectors.