Genomic mutation signatures in primary breast cancer and their axillary metastatic lymph nodes

Abstract Breast cancer is one of the most common malignant tumors in women all over the world. Metastasis represents a major adverse progression of breast cancer, resulting in poor survival duration. Axillary lymph node metastasis is often the first step of systemic metastasis process of breast cancer. However, the mechanism of lymph node metastasis and the genomic signatures of primary breast tumors and lymph node metastasis are still under exploration. Whole exome sequencing was applied to primary breast cancer, axillary metastatic lymph nodes, and white blood cells from 10 Chinese women patients in our study. Single nucleotide variants (SNVs) and copy-number variants (CNVs) were compared between primary tumors and lymph nodes for individual patients. There are somatic SNVs (average 5.58 ± 2.56 per megabase) in primary breast cancers and somatic SNVs (average 5.46 ± 2.66 per megabase) in axillary metastatic lymph nodes were identified, which is corresponding to a semblable mutation burden in two malignant sites (P = 0.81). No difference was found in CNVs (P = 0.33). In primary breast cancer, somatic SNVs (48.12 ± 13.80%) and CNVs (61.72 ± 35.00%) were overlapping with somatic SNVs (49.43 ± 12.30%) and CNVs (72.01 ± 24.31%) in axillary metastatic lymph nodes. Nine genes were screened for significant specific mutations in primary tumors, and 15 genes were significantly mutated in metastatic lymph nodes. Using MutSigCV screening, it was found that HRNR and AHNAK2 are lymph node metastasis-specific genes. In our study, primary breast tumors are directly related to axillary lymph node metastases together and there are most SNVs and CNVs which were overlapping in primary and metastatic sites. These variants which are overlapping is closely related to the metastatic process of tumor invasion with early genetic variability. This is the first time to prove the concept of polyclonal metastatic model and in this model more than one clone migrates establish the metastases to axillary lymph nodes. This study was approved by the institutional review board (IRB) of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, China (approval No. NCC2016G-030) on March 3, 2016.