Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression
Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression
复制标题
DOI：
10.1530/erc-14-0147
复制
发表时间：
2014-12-01
影响因子：
3.9
通讯作者：
Jung, Chan Kwon
中科院分区：
文献类型：
--
作者：
Kim, Min-Hee;Bae, Ja Seong;Jung, Chan Kwon
BRAF V600E 突变是甲状腺癌中最常见的基因改变。然而，其临床病理意义和克隆突变频率仍不清楚。为了澄清不一致的结果，我们研究了 BRAF V600E 等位基因频率与经典乳头状甲状腺癌 (PTC) 临床病理特征之间的关联。对两组独立的经典 PTC 患者的肿瘤组织进行手动显微解剖，并使用定量焦磷酸测序分析是否存在 BRAF 突变以及突变等位基因频率。为了进行外部验证，对癌症基因组图谱 (TCGA) 数据进行了分析。在训练集中的 321 个经典 PTC 中，有 264 个 (82.2%) 发现了 BRAF V600E 突变。 BRAF V600E 的存在仅与甲状腺外扩展和不存在甲状腺炎相关。在 BRAF V600E 阳性肿瘤中，突变等位基因频率为 BRAF 等位基因总数的 8% 至 41%（中位数为 20%），并且与肿瘤大小和转移淋巴结的数量直接相关。突变等位基因丰度高 (>= 20%) 的 PTC 中淋巴结转移比突变等位基因丰度低的 PTC 更常见 (P=0.010)。这些结果通过验证数据集 (n=348) 分析得到强化，但未在 TCGA 数据集中重现。在 BRAF 突变普遍存在的人群中，BRAF 突变的定量分析可以提供有关肿瘤行为的额外信息，而定性分析无法反映这一点。尽管如此，在将突变等位基因百分比视为预后因素之前，还需要进行前瞻性研究。
The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (>= 20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.