Germline mutation PTCH2 1172-1173delCT in Chinese population with early-onset breast cancer

e13049 Background: Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The peak age of breast cancer in China is about 40 years old, 10 years ahead of that in Europe and the United States. PTCH2 was characterized as susceptibility gene in early-onset breast cancer by whole exons sequencing in preliminary work. PTCH2 performs as a tumor suppressor in the Hedgehog signaling pathway, but it has never been reported in breast cancer. Methods: 259 women with early-onset breast cancer and 571 women with non-early-onset breast cancer with peripheral blood samples were included for genetic testing. According to the ACMG guidlines, PTCH2 1172-1173delCT was defined as likely pathogenic mutation. To make an in-depth exploration of the function and molecular mechanism of PTCH2 gene, we performed experiments at molcular, cellular and animal level. Results: The frequency 2.3%(6/259)of PTCH2 germline mutation in early-onset breast cancer was significantly higher than that(2/571) in non-early-onset breast cancer( P ＜ 0.05), and increased with the age at diagnosis younger. Bioinformatics analysis showed that the patients with lower expression of PTCH2 had worse prognosis. PTCH2 knockout cells lines promoted the cell proliferation and enhanced the ability of colony formation and tumorigenic ability of nude mice. Furthermore, the expression level of pten in the PTCH2 knockout cell lines was significantly downregulated. Conclusions: Patients with PTCH2 1172-1173delCT mutation had aggressive clinicopathological characteristics and worse prognosis. As a tumor suppressor gene, PTCH2 may promote the incidence of early-onset breast cancer by downregulating the expression of pten and cross-regulating Hedgehog and PI3K/AKT signaling pathways. PTCH2 could be acted as a diagnostic and prognostic biomarker for early-onset breast cancer.