Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
Mod Pathol. 2018 Nov;31(11):1661-1674. doi: 10.1038/s41379-018-0081-z. Epub 2018 Jun 26.
Metaplastic breast carcinomas comprise a histologically heterogenous group of tumors. Although most are triple (estrogen/progesterone receptor, HER2) negative, these rare tumors are clinicopathologically distinct from other triple negative carcinomas and may be aggressive with worse chemotherapy responses. On the other hand, metaplastic carcinomas are histologically diverse, which is reflected in gene expression differences among subtypes. Whether metaplastic carcinomas are genetically distinct from other triple negative cancers and whether genetic differences underlie histologic subtypes remains poorly understood. We sequenced 408 cancer-related genes in 28 metaplastic carcinomas, including chondroid matrix-producing carcinomas (n = 10), spindle cell carcinomas (n = 5), and carcinomas with squamous (n = 5), mixed spindle/squamous (n = 5), and mixed metaplastic (n = 3) differentiation. Metaplastic carcinomas were highly enriched for PIK3CA/PIK3R1 (61%) and Ras-Map kinase (25%) pathway aberrations compared to other triple negative carcinomas (TCGA dataset 14%, p < 0.001 and 7%, p = 0.005, respectively) and harbored a high frequency of TP53 (64%) and TERT promoter (25%) mutations, but this varied among subtypes. Chondroid-matrix producing carcinomas lacked PI-3 kinase and Ras-Map kinase aberrations and TERT promoter mutations, compared to 100%, 39%, and 39% of non-matrix-producing tumors, respectively. TERT promoter mutations were enriched (47%) in spindle cell carcinomas and tumors with squamous or spindle/squamous differentiation. Spindle cell carcinomas lacked TP53 mutations, in contrast to other subtypes (78%, p = 0.003). Separate analysis of paired ductal carcinoma in situ and metaplastic carcinoma revealed shared clonality in all cases (n = 8). Activating PI-3 kinase and Ras pathway mutations were early events, and inactivating mutations in tumor suppressors including RB1, CDKN2A, and TP53 were associated with invasion in individual cases. Metaplastic components of two tumors showed genetic progression from separately sequenced paired invasive ductal carcinoma. The findings suggest that metaplastic carcinomas are genetically distinct from other triple negative breast cancers and highlight genetic heterogeneity that broadly correlates with histologic subtype. Heterologous elements progress from associated ductal carcinoma.
化生性乳腺癌是一组组织学异质性的肿瘤。尽管大多数为三阴性（雌激素/孕激素受体、HER2），但这些罕见的肿瘤在临床病理上与其他三阴性癌不同，并且可能具有侵袭性，化疗反应更差。另一方面，化生性癌在组织学上具有多样性，这反映在亚型之间的基因表达差异上。化生性癌是否在遗传上与其他三阴性癌不同，以及遗传差异是否是组织学亚型的基础，目前仍知之甚少。我们对 28 例化生性癌（包括软骨样基质生成癌[10 例]、梭形细胞癌[5 例]、鳞状分化癌[5 例]、混合梭形/鳞状分化癌[5 例]和混合化生性癌[3 例]）进行了 408 个癌症相关基因的测序。与其他三阴性癌（TCGA 数据集为 14%，p<0.001 和 7%，p=0.005）相比，化生性癌中 PIK3CA/PIK3R1（61%）和 Ras-MAP 激酶（25%）通路异常更为丰富，并且还具有高频的 TP53（64%）和 TERT 启动子（25%）突变，但在不同亚型中存在差异。与非基质生成肿瘤的 100%、39%和 39%相比，软骨样基质生成癌缺乏 PI-3 激酶和 Ras-MAP 激酶异常和 TERT 启动子突变。TERT 启动子突变在梭形细胞癌和具有鳞状或梭形/鳞状分化的肿瘤中丰富（47%）。与其他亚型（78%，p=0.003）相比，梭形细胞癌缺乏 TP53 突变。对原位导管癌和化生性癌的配对分析显示，所有病例（n=8）均具有克隆性。激活的 PI-3 激酶和 Ras 通路突变是早期事件，而肿瘤抑制基因 RB1、CDKN2A 和 TP53 的失活突变与个别病例的浸润有关。两个肿瘤的化生性成分显示出从单独测序的配对浸润性导管癌中遗传进展。研究结果表明，化生性癌在遗传上与其他三阴性乳腺癌不同，并突出了与组织学亚型广泛相关的遗传异质性。异源成分从相关的导管癌进展而来。
