PDF(Sci-hub)
Abstract：
Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
摘要：
化生性乳腺癌（MBC）和子宫癌肉瘤（UCS）是罕见的侵袭性癌症，特征是腺癌和显示间质/肉瘤样分化的区域的混合物。我们试图定义MBC和UCS是否具有相似的遗传改变模式，以及MBCs和UCSs的不同组织学成分是否呈克隆相关。重新分析来自MBC（n=35）和UCSs（n=57，癌症基因组图谱）的全外显子组测序（WES）数据，以定义体细胞遗传改变，改变的信号通路，突变签名，同源重组DNA修复缺陷（HRD）的基因组特征。此外,另外一组MBCs（n=11）和UCSs（n=6）的癌性和肉瘤性成分分别进行显微解剖并接受WES，并评估了它们的克隆相关性。MBC和UCS具有影响TP53，PIK3CA，和PTEN,基因拷贝数改变的相似模式，以及影响上皮间质转化（EMT）相关Wnt和Notch信号通路的变化的富集。观察到差异，然而,包括与UCS相比，MBCs中FAT3和FAT1体细胞突变的患病率明显更高，反过来,与MBC相比，UCS明显更频繁地携带影响FBXW7和PPP2R1A以及HER2扩增的体细胞突变。发现HRD的基因组特征和影响真正HRD相关基因的双等位基因改变在MBC中比在UCS中更普遍。在所有病例中，MBCs和UCSs的不同组织学成分是克隆相关的，肉瘤成分可能源于样本中癌成分的次要亚克隆，具有可解释的克隆进化时间顺序。尽管相似的组织学特征和途径受遗传改变的影响，UCS在FBXW7和PPP2R1A突变的基础上与MBCs不同，HER2扩增,缺乏人力资源开发，支持这样的观点，即这些实体不仅仅是在不同解剖部位的相同肿瘤类型的表型。
