Exploration Of Genes Associated With Axillary Lymph Node Metastasis In Chinese Women With Breast Cancer

BackgroundAccording to the latest epidemiological data,breast cancer has become the first malignant tumor in the world in terms of incidence.Once a breast cancer patient has metastasized,it often indicates a poor prognosis and a short survival time.Axillary lymph node metastasis often represents the first step of the metastatic process.However,the mechanism of lymph node metastasis and the genomic signatures of the primary breast tumor and the lymph node metastasis is still under exploration.MethodsWe selected 10 breast cancer patients from a Chinese Han population,and 10 patients also had axillary lymph node metastasis.After surgery,we took the corresponding breast cancer tissue from each patient with axillary metastatic lymph node tissue for whole exome sequencing.Single nucleotide variants(SNVs)and copy-number variants(CNVs)were generated and compared between primary tumor and lymph node within individual patients.The significant differences in the number of SNVs and the length of CNVs were determined by Student’s t-tests.ResultsThe samples were sequenced to high,uniform coverage.An average of 5.58±2.56 somatic SNVs per megabase(Mb)in primary tumors and 5.46±2.66 somatic SNVs/Mb in lymph node metastases were identified,corresponding to similar mutation burden between two malignant sites(p=0.81).There was also no difference in the length of CNVs(p=0.33).Moreover,48.12%± 13.80%of somatic SNVs and 61.72±35.00%of CNVs in primary tumors,and 49.43%± 12.30%of somatic SNVs and 72.01 ±24.31%of CNVs in lymph node metastases were overlapping.In breast primary tumors,genes ZNF697,AHNAK,TXNDC2,TCHH,UBQLN1,PCDHA8,ZNF254,QRICH2 and ZNF888 were screened for significant mutations.And in metastatic lymph nodes,TCHH,HRNR,ZAN,FRG1BP,FRG1DP,AHNAK,KRTAP4-6,AHNAK2,ZNF343,ZAN,RPTN,POM 121,KRTAP10-4,GOLGA6L2,and TAS2R30 had significant mutations.Through screening,we identified two specific genes associated with axillary lymph node metastasis in breast cancer,AHNAK2 and HRNR genes,respectively.ConclusionOur study reveals a direct genomic lineage between the primary breast tumor and axillary lymph node metastases and further show that most SNVs and CNVs were overlapping in these two malignant sites.The overlapping variants are associated with tumor invasion,which supports the early genetic variability in the metastatic process.These results prove the concept of the multi-clonal metastatic model for the first time,in which more than one clones migrate into the axillary lymph node to establish the metastases.