Prevalence of genetic alterations in basal cell carcinoma patients resistant to Hedgehog pathway inhibitors: a systematic review

Basal cell carcinoma (BCC) is a prevalent form of skin cancer that can be localized or metastatic. Current evidence supports the use of Hedgehog (Hh) pathway inhibitors for locally advanced or metastatic BCC with resistance due to genetic alterations in the Hh pathway. This systematic review evaluated the prevalence of genetic alterations in Hh pathway genes in BCC.
We conducted a comprehensive search across four databases: PubMed, EMBASE, SCOPUS and the Cochrane Library. We included articles reporting genetic alterations in patients with locally advanced or metastatic BCC resistant to Hh pathway inhibitors.
We included three prospective cohort studies encompassing 27 samples, all of which were resistant to vismodegib treatment. The most prevalent genetic mutations in the Hh pathway were in PTCH1, SMO and TP53, with a pooled prevalence of 44.44%.
This systematic review highlights the prevalence of genetic alterations in the Hh pathway in BCC and offers insights into the mechanisms involved in treatment resistance. Understanding the high resistance rates of these genes may facilitate the development of more effective targeted therapies for BCC.
The recent literature found no study established the prevalence and genetic alterations which related systemic treatments in treating advanced basal cell carcinoma. This study found that PTCH1, SMO and TP53 were the most prevalent genetic mutations in the Hedgehog pathway. As a result, our results may influence further therapeutic strategies, resulting in disruption of the resistance mechanisms.

基底细胞癌（Basal cell carcinoma, BCC）是一类常见皮肤癌，可分为局限性与转移性两类。现有证据表明，针对因Hedgehog（Hh）通路基因变异产生耐药性的局部晚期或转移性BCC患者，可采用Hh通路抑制剂进行治疗。本系统综述旨在评估BCC患者Hh通路基因的变异发生率。
我们对PubMed、EMBASE、SCOPUS及Cochrane Library四大数据库开展了全面检索，纳入的文献需报告经Hh通路抑制剂治疗后产生耐药的局部晚期或转移性BCC患者的基因变异情况。
最终纳入3项前瞻性队列研究，共包含27份样本，所有样本均对维莫德吉（vismodegib）治疗产生耐药。Hh通路中最常见的基因突变位点为PTCH1、SMO与TP53，合并发生率为44.44%。
本系统综述明确了BCC患者Hh通路基因变异的发生率，并为阐明治疗耐药的相关机制提供了新视角。明晰上述基因的高耐药性特征，有助于推动针对BCC的更高效靶向治疗方案研发。
现有研究显示，目前尚无针对晚期基底细胞癌全身治疗相关基因变异及发生率的专项研究。本研究发现，Hedgehog通路中最常见的基因突变仍为PTCH1、SMO与TP53。综上，本研究结果可为后续治疗策略优化提供参考，助力破解耐药机制。