217P - Clinical and molecular features of PTCH1 mutant in solid tumors

Background

PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway. Hh signaling was reported to modulate the tumor microenvironment by increasing immune checkpoint expression and promoting an inflammatory environment. Mutations of PTCH1 are potential therapeutic targets, Hh pathway inhibitor has been developed as a treatment for patients with advanced solid tumors. It is thus important to understand the genomic landscape of PTCH1 mutation. Here, we explored PTCH1 mutation profiles in Chinese solid tumors.

Methods

Next-generation sequencing of 551-gene profiling was performed to analyze postoperative tissues from 22312 Chinese solid tumors in 2019-2022. Somatic mutations and copy number variations were detected following the standard operating procedure.

Results

PTCH1 mutations were present in 3.1% of patients with advanced solid tumors, a total of 791 PTCH1 somatic mutations were detected in 684 tumor samples. The higher frequency cancer type contained lung cancer(n=239), colorectal cancer(n=137), and stomach cancer(n=60). Of 791 PTCH1 mutations, missense mutations(65%,n=514) were more observed, and 25% were loss of function (LOF) mutations, including frameshift(n=124), nonsense(n=50), splicing(n=23) mutations. Exon 23, exon1 and exon22 of PTCH1 were the main mutational hotspot regions found, with p.S1203Afs*52 (n=26), p.R1308Efs*64 (n=22), p.R602* (n=11), p.Y1316Tfs*56 (n=11) being the most frequent mutations in our study. There was a significant statistical difference in TMB values that the PTCH1 mutant group was higher than the PTCH1 wild-type group (39 vs. 5, p < 0.001), and patients who presented with two or more PTCH1 mutations with higher compared with those patients carried only a single mutation (129 vs. 29, p < 0.001). TMB in PTCH1 frameshift_variant tumors (53, 0–672) was significantly higher than TMB in PTCH1 splice variant tumors (15, 0–60; P < 0.05). The proportion of PTCH1 alterations in MSI-H tumors was higher than those without mutations (22% vs. 1%, p < 0.001).

Conclusions

In our study, PTCH1 mutations are present in 3.1% of solid tumors, and mostly occurred in exon 23, exon1, and exon22. PTCH1 mutant tumors tended to be associated with higher TMB values (39 vs. 5), therefore, Hh pathway inhibitor combined immunotherapy may be considered in the future.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.