Abstract P3-05-31: PVT1, CASC16, TNFRSF13B and NAMPT may be the key genes correlated with recurrence and metastasis of breast cancer

Abstract Background: It is vital to find the risk genes and loci related to recurrence and metastasis in breast cancer (BC) patients. The Genome-wide association study (GWAS) can detect the risk of single nucleotide polymorphism (SNP) and help us understand the mechanism of disease progression by analyzing the SNP information of the whole genome. At present, GWAS have identified several genetic susceptibility SNPs for BC, but it is unclear about its significance in the recurrence and metastasis of BC patients. Therefore, in this study we aimed to identify the risk SNPs related to recurrence and metastasis of BC based on GWAS analysis. Methods: This study adopts a two-stage GWAS research strategy. In the first stage, according to propensity score matching, we chose 97 pairs of BC patients with or without recurrence and metastasis who were treated in Shandong Cancer Hospital and Institute from November 2013 to April 2014. Their peripheral blood samples were collected and DNA was extracted for genome-wide detection by Illumina ASA chip. The SNP loci related to recurrence and metastasis of BC were obtained by logistic regression analysis of GWAS. In the second stage, 854 BC patients from the same hospital were verified from May 2014 to June 2015. The SNP genotyping was detected by time-of-flight mass spectrometry to verify its correlation with recurrence and metastasis of BC. The SNP loci and their corresponding genes and pathways were analyzed using DAVID (https://david.ncifcrf.gov/) online enrichment analysis website. Results: In the first stage, 191 SNPs were obtained from GWAS analysis (P< 0.001). Based on these SNPs and their corresponding genes, we further found that glutamatergic synaptic transmission may be related to BC recurrence and metastasis through GO analysis. Similar results were found in calcium signaling pathway and insulin secretion pathway through KEGG enrichment analysis. And 21 SNPs were screened for their association with the tumor evolution process and whether they are located in the gene coding functional region. In the second stage, Cox regression analysis showed that the genotyping of the four SNPs was consistent with the results of GWAS analysis, and these SNPs are located in the intron region of the gene. Specifically, compared with homozygous AA, BC patients carrying TNFRSF13B rs4273077(AG/GG) and PVT1 rs10108514(AG/GG) had a 26% (HR: 0.74, 95%CI: 0.54-1.01) and 27% (HR: 0.73, 95%CI: 0.54-0.98) reduced risk of recurrence and metastasis, respectively; compared with homozygous CC, patients with BC carrying NAMPT rs4730155(CT/TT) had a 35% (HR: 0.65, 95%CI: 0.45-0.93) reduced risk of recurrence and metastasis; while compared with CASC16 rs12920540(CA/AA), BC patients with homozygous CC has a 52% (HR: 1.52, 95%CI: 1.06-2.18) increased risk of recurrence and metastasis. Analysis of TCGA and GTEX databases showed that the expression levels of PVT1 and CASC16 in breast tumors were significantly higher than those in normal tissues and matched para-cancerous tissues (P< 0.001), whereas the expression level of NAMPT in breast tumors was significantly lower than that in normal tissues (P< 0.001). No significant difference was shown about the expression level of TNFRSF13B between breast tumor and normal tissues or matched para-cancerous tissues (P≥0.05). Conclusion: Our study suggested that PVT1, CASC16, TNFRSF13B and NAMPT may be correlated with the risk of recurrence and metastasis of BC. Glutamatergic synaptic transmission, calcium signaling pathway and insulin secretion pathway may be involved in BC recurrence and metastasis. Citation Format: Huihui Li, Sha Yin, Shujuan Sun, Qiaorui Tan, Xiaochu Man, Jie Huang, Xuemei Xie. PVT1, CASC16, TNFRSF13B and NAMPT may be the key genes correlated with recurrence and metastasis of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-31.