YAP1 and downstream gene alterations in metastatic breast cancer.

e13121 Background: Metastatic breast cancer remains a major clinical challenge, characterized by poor prognosis and limited therapeutic options. The incidence of metastatic female breast cancer increased from 5.8 to 7.9 per 100,000 females from 2001 to 2021. The Hippo pathway effector YAP1 plays a critical role in driving tumor growth and metastasis in many cancers including breast but little is known about the gene-specific changes that occur when breast cancers have metastasized. This study aimed to investigate the extent of genomic alterations, including copy number alterations (CNAs) and mutations, in YAP1 and its downstream genes in metastatic breast cancer compared to nonmetastatic breast cancer. Methods: Genomic data for the YAP1 gene and its downstream target genes (CTGF, Cyr61, MCL-1, TOP2A, FOSL2, and ANKRD1) were obtained from cBioPortal. This included mutation data and CNA data, considering both amplifications and deletions as CNA events. The chi-square test was performed using GraphPad Prism 10 to compare the frequencies of mutations and CNAs between metastatic and non-metastatic breast cancer cases. Results: A total of 2390 samples of metastatic breast cancer and 9289 samples of non-metastatic breast cancer were analyzed for mutations. Among them, a significantly higher percentage of mutations in the YAP1 (P ≤ 0.0001), ANKRD1 (P ≤ 0.0001), MCL-1 (P ≤ 0.0001), and TOP2A (P ≤ 0.0001) genes was observed in metastatic breast cancer compared to non-metastatic breast cancer. Evaluating CNAs in 2197 cases in the metastatic breast cancer group compared to 9289 cases in the non-metastatic breast cancer group demonstrated a significantly higher frequency of CNAs in the YAP1 ( P ≤ 0.0001), Cyr61 (P ≤ 0.0001), CTGF ( P ≤ 0.0001), ANKRD1 ( P ≤ 0.0001), TOP2A (P ≤ 0.0001) and FOSL2 (P ≤ 0.0001) genes among metastatic breast cancer. Conclusions: This study revealed significant genomic alterations in the YAP1 gene and its downstream genes in metastatic breast cancer. These findings highlight the importance of the YAP1 pathway in breast cancer metastasis and suggest that targeting this pathway may have therapeutic potential for primary and metastatic breast cancer. Frequency of mutations and copy number alterations (CNAs) in metastatic vs. non-metastatic breast cancer. Gene Metastatic Breast Cancer Mutation Frequency (%) Non-Metastatic Breast Cancer Mutation Frequency (%) P-value Metastatic Breast Cancer CNA Frequency (%) Non-Metastatic Breast Cancer CNA Frequency (%) P-value YAP1 0.75 0.17 <0.0001 5.1 1.18 <0.0001 CTGF 0.13 0.18 0.781 5.42 0.65 <0.0001 Cyr61 0.17 0.16 0.999 3.9 0.65 <0.0001 MCL-1 0.63 0.11 <0.0001 10.74 11.93 0.121 ANKRD1 1.17 0.09 <0.0001 1.96 0.25 <0.0001 TOP2A 0.96 0.18 <0.0001 8.06 3.6 <0.0001 FOSL2 0.17 0.1 0.317 3.64 0.62 <0.0001