Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women. Various mechanisms are involved in the initiation and progression of breast cancer. Metabolic dysregulation has been associated with increasing breast cancer incidence and mortality. However, little is known about how metabolic disease regulates the development and progression of breast cancer at the molecular level. Here, using a hybridization capture-based panel including 124 cancer-associated genes, we performed targeted next-generation sequencing of tumor tissues and matched blood samples from 20 postmenopausal patients with primary breast cancer, in which 6 cases suffered from preexisting metabolic disorders including hypertension, type 2 diabetes, and coronary heart disease. We took only the protein-altering variants and identified 170 somatic mutations of 59 genes. Among these, 40 mutated genes were found in the metabolic disease group, and 33 mutated genes were found in the non–metabolic disease group. Importantly, nonsynonymous mutations of 26 genes (MSH3, BRAF, MLH3, MTOR, DDR2, ALK, etc.) were uniquely present in the metabolic disease group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to investigate biological functions and key pathways of somatic mutations. TP53, PIK3CA, and PTEN were the top three commonly mutated genes at a higher frequency compared with the Cancer Genome Atlas (TCGA) data, and several novel but infrequent mutations in other genes were also found. Although further studies are required to validate these variants, our results are the first to suggest a specific molecular profile of breast cancer with preexisting metabolic disease.

乳腺癌是最常见的癌症，也是女性癌症死亡的主要原因。乳腺癌的发生和发展涉及多种机制。代谢失调与乳腺癌的发病率和死亡率增加有关。但是，关于代谢性疾病如何在分子水平上调控乳腺癌的发展和进展知之甚少。在这里，我们使用包含124个与癌症相关的基因的杂交捕获技术，对20例绝经后原发性乳腺癌患者的肿瘤组织和匹配的血液样本进行了靶向的下一代测序，其中6例患有既往的代谢性疾病，包括高血压，2型糖尿病和冠心病。我们仅采用了改变蛋白质的变体，并鉴定出59个基因的170个体细胞突变。其中，在代谢疾病组中发现了40个突变基因，在非代谢性疾病组中发现了33个突变基因。重要的是，在代谢疾病组中独特地存在26个基因的非同义突变（MSH3，BRAF，MLH3，MTOR，DDR2，ALK等）。进行了基因本体论（GO）和《京都议定书》的基因大全和基因组富集分析，以研究体细胞突变的生物学功能和关键途径。与癌症基因组图谱（TCGA）数据相比，TP53，PIK3CA和PTEN是频率最高的前三个常见突变基因，并且在其他基因中也发现了一些新颖但不常见的突变。尽管需要进一步的研究来验证这些变体，