乳腺叶状肿瘤(PT)是一种罕见的双相肿瘤。最近的下一代测序分析揭示了PT的新遗传改变,但缺乏对它们与不同PT特征和结果的关系的进一步表征。这里,使用靶向测序,我们检查了88个PT样本中的90个反复改变或癌症相关基因(包括49个良性,25个边界线和14个恶性PT)。23个基因在至少8.0%的病例中显示出改变。随着PT等级的增加,变化显着增加(p=0.033),特别是拷贝数改变。前十位的改变是TERT启动子(58.0%),MED12(53.4%),RARA(22.8%),FLNA(19.3%),SETD2(15.9%),SYNE1(18.2%),PCLO(15.9%),KMT2D(14.3%),CDKN2A(15.9%)和DNAH11(14.8%)。CDKN2A/B中的变更,EGFR,TP53,PIK3CA,PTEN和ARID1B(p≤0.039)与较高的等级相关。分析基于常见途径的改变表明细胞周期途径和表观遗传改变与较高PT等级的显着相关性(分别为p=0.036和0.075)。有趣的是,复发与肿瘤分级无关,但与RARA突变的存在(p=0.011)和表观遗传途径的改变(p=0.031)有关。对PT的同步对分析显示,具有分歧MED12突变的基因突变更多差异。相比之下,复发样本显示与原发性肿瘤相似的遗传改变.总之,我们对不同等级PT的遗传改变进行了表征,并证实了早期研究中观察到的复发性改变.此外,目前的数据暗示了细胞周期的作用,PT复发和肿瘤发生的表观遗传学和RARA变化。
Phyllodes tumour (PT) of breast is a rare biphasic neoplasm. Recent next generation sequencing analyses had revealed novel genetic alterations in PT but lacked a further characterisation of their relationship to different PT features and outcome. Here, using targeted sequencing, we examined a panel of 90 recurrently altered or cancer related genes in 88 PT samples (including 49 benign, 25 borderline and 14 malignant PT). Twenty-three genes showed alterations in at least 8.0% of cases. Alterations were significantly higher with an increasing grade of PT (p=0.033), particularly for copy number alterations. The top ten alterations were TERT promoter (58.0%), MED12 (53.4%), RARA (22.8%), FLNA (19.3%), SETD2 (15.9%), SYNE1 (18.2%), PCLO (15.9%), KMT2D (14.3%), CDKN2A (15.9%) and DNAH11 (14.8%). Alterations in CDKN2A/B, EGFR, TP53, PIK3CA, PTEN and ARID1B (p≤0.039) were associated with a higher grade. Analysing alterations based on common pathways indicated a significant correlation of cell cycle pathway and epigenetic alterations with a higher PT grade (p=0.036 and 0.075 respectively). Interestingly, recurrences were not correlated with tumour grade, but related to the presence of RARA mutation (p=0.011) and the absence of alterations in epigenetic pathway (p=0.031). Analysis of synchronous pair of PT showed more differences in gene mutations with divergent MED12 mutation. By contrast, the recurrent samples showed similar genetic alterations as the primary tumours. In summary, we characterised genetic alterations in PTs of different grades and confirmed the recurrent alterations observed in earlier studies. In addition, current data implicated the roles of cell cycle, epigenetic and RARA changes in PT recurrence and tumourogenesis.