Mutation of the PTCH1 gene predicts recurrence of breast cancer

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.

Nevoid Basal Cell Carcinoma Syndrome: PTCH1 Mutation Profile and Expression of Genes Involved in the Hedgehog Pathway in Argentinian Patients

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCC), mainly caused by PTCH1 gene mutations. Our current study aimed to establish (1) PTCH1 germinal and somatic mutational status, (2) component and Hedgehog (HH) pathway targets gene expression patterns, and (3) profile variations according to the genetic background in BCC and normal surrounding skin (NSS). We collected 23 blood and 20 BCC patient samples and analyzed the PTCH1 gene using bidirectional sequencing and multiplex ligation-dependent probe amplification. Quantitative PCR was used to determine the mRNA expression levels of PTCH1, SMO, GLI3, and CCND1 in paired samples of BCC and NSS from 20 patients and four non-NBCCS skin controls (C). Our analyses identified 12 germline and five somatic sequence variants in PTCH1. mRNA levels of PTCH1, SMO, and GLI3 were higher in NSS compared to C samples, reaching maximum values in BCC samples (p < 0.05). NSS with PTCH1 germline mutations had modified SMO, PTCH1, and GLI3 mRNA levels compared to samples without mutation (p < 0.01). Two PTCH1 mutations in BCC led to an increase in PTCH1, SMO, and GLI3, and a decrease in CCND1 mRNA levels (p < 0.01 vs. BCC with germline mutation only). These results indicate that besides PTCH1, other genes are responsible for NBCCS and BCC development in a population exposed to high UV radiation. Additionally, the mutational events caused increased expression of HH-related genes, even in phenotypically normal skin.