Breast cancer ovarian metastases show increased activity of GPCR pathways

作者：Laura Savariau, Ye Qin, Osama Shiraz Shah, Ahmed Basudan, Chris Merkel, Saumya D. Sisoudiya, Smruthy Sivakumar, Ethan Sokol, Olivia McGinn, Zheqi Li, Tiantong Liu, Nilgun Tasdemir, Pooja Tallapaneni, Lan Coffman, Esther Elishaev, Jennifer M. Atkinson, Peter C. Lucas, Adrian V. Lee, Steffi Oesterreich · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.30.741805 · 研究领域：Ovarian cancer diagnosis and treatment、Breast Lesions and Carcinomas、Cancer, Stress, Anesthesia, and Immune Response

Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showe...