Mutation of the PTCH1 gene predicts recurrence of breast cancer

Abstract

Breast cancer is the most common cancer in women, and some patients develop recurrence after standard therapy. Effective predictors are urgently needed to detect recurrence earlier. The activation of Hedgehog signaling in breast cancer is correlated with poor prognosis. PTCH1 is an essential membrane receptor of Hedgehog. However, there are few reports about mutations in Hedgehog genes in breast cancer. We conducted a comprehensive study via an experimental and bioinformatics approach to detect mutated genes in breast cancer. Twenty-two breast cancer patients who developed recurrence within 24 months postoperatively were enrolled with 22 control cancer patients. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the mutated genes. Mutations were identified in 44 breast cancer specimens, and the most frequently mutated genes were BRCA2, APC, ATM, BRCA1, NF1, TET2, TSC1, TSC2, NOTCH1, MSH2, PTCH1, TP53, PIK3CA, FBXW7, and RB1. Mutation of these genes was correlated with protein phosphorylation and autophosphorylation, such as peptidyl-tyrosine and protein kinase C phosphorylation. Among these highly mutated genes, mutations of PTCH1 were associated with poor prognosis and increased recurrence of breast cancer, especially mutations in exons 22 and 23. The public sequencing data from the COSMIC database were exploited to predict the functions of the mutations. Our findings suggest that mutation of PTCH1 is correlated with early recurrence of breast cancer patients and will become a powerful predictor for recurrence of breast cancer.

Hedgehog Signaling and Truncated GLI1 in Cancer

“…As expected, the presence of SHH restores canonical signaling and precludes the PTCH1 interaction with Cyclin B1, permitting its nuclear translocation and completion of mitosis [89]. The multiplicity of PTCH1 tumor-suppressive functions supports PTCH1 mutations as a strong predictor of breast cancer recurrence meriting further study [16].…”

“…Deregulated HH signaling is typified by basal cell carcinoma (BCC) and medulloblastoma, two well-recognized cancers with protein mutations of HH pathway components [ 13 , 14 , 15 ]. In addition, dysregulation of HH signaling activity has also been linked to the pathologies of breast, lung, pancreas, and prostate cancers [ 4 , 16 , 17 , 18 ]. Due to the importance of HH signaling in human cancer, attempts to therapeutically target this pathway have been extensive, which have resulted in three US FDA-approved inhibitors available for use in cancers to date: arsenic trioxide, vismodegib/GDC-0449, and sonidegib/LDE-225 [ 19 ].…”

Analysis of LAGEs Family Gene Signature and Prognostic Relevance in Breast Cancer

“…This was accomplished by searching the LAGE gene family’s expression list using Venny vers. 2.1 and then doing a Cytoscape analysis [ 36 , 37 , 38 , 39 , 40 ]. The second part determined the biological processes, disease biomarker networks, and breast neoplasm cell-cell signaling pathways using the MetaCore analysis ( , accessed on 30 November 2020).…”

Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models

“…Short- and long-term SARS-CoV/SARS-CoV-2-infected ferrets and mock controls were compared. The top 10% of differentially expressed genes (DEGs) with a higher degree of expression in SARS-CoV/SARS-CoV-2-infected groups were analyzed as described previously ( Wang et al, 2017a ; Wang et al, 2019 ; Wang et al, 2020a ; Yang et al, 2020 ). A p value of 0.05 was set, an adjusted false discovery rate (FDR) was followed, and a list of genes with significantly different expressions was used as input to the GO database for constructing biological networks and their associated biological processes and diseases ( Ashburner et al, 2000 ).…”