Genetic Profiling of Breast Cancer with and Without Preexisting Metabolic Disease

Abstract

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.