PTCH1 mutation

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

This Indian study identified novel somatic mutations and fusion genes in PTC, revealing a distinct genomic landscape with implications in precision diagnostics and personalized therapies. NGS with intraoperative live sampling shows promise in prognostication and therapeutic optimization of advanced/metastatic PTC cases.

Heterogeneity in the hormone receptor and HER2 status of SBBC poses unique therapeutic challenges. Future studies should aim to identify the optimal management strategy for this disease.

Genomic evaluation has been performed in neoplasms from one individual with cutaneous BCC in situ and metastatic BCC; like other variants of BCC, an aberration of the PTCH1 gene was observed. In contrast to his liver metastasis, the in situ carcinoma had a lower tumor mutational burden, lacked programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) amplification and had a distinct PTCH1 mutation, suggesting that the in situ BCC of his skin and the metastatic BCC of his liver were derived from different clones of cells.

BCC is characterized by low immunogenicity, which hinders immune response and contributes to treatment challenges. Enhanced understanding of the epidemiology, risk factors, and pathogenesis of locally advanced BCC, along with the development of targeted therapeutic approaches such as hedgehog pathway inhibitors, is essential for effectively managing this prevalent carcinoma and improving patient outcomes.

P1, N=37, Completed, Case Comprehensive Cancer Center | Active, not recruiting --> Completed

The mutated gene in this patient was determined to be the ELP1 gene located on chromosome 9. This patient's ELP1 gene mutation may contribute to the development of multiple nevoid basal cell carcinomas on the face.

P2, N=124, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Oct 2024 --> Jan 2028 | Trial primary completion date: Oct 2024 --> Jan 2026

Germline SUFU mutation carriers should be recognized as a distinct group of patients carrying specific health risks, independent of meeting the BCNS criteria. Phenotypic prediction based on the specific SUFU mutation seems unfeasible. It is of utmost importance that the less apparent MHIBCC phenotype is recognized, to provide (second generation) germline SUFU mutation carriers appropriate healthcare.

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor pts was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

Molecular screening of patients with GS who do not fulfill Evan's diagnostic criteria should only be offered in first intention to patients under 30 years of age. After 30 years, a careful clinical examination and complementary radiological exams should be enough to eliminate the diagnosis of GS among patients who do not fulfill diagnostic criteria.

This study expands the mutation spectrum of PTCH1 in GS and facilitates the early diagnosis and screening of GS. PTCH1 [c.3512_3526del (p.1171_1176del)] may cause structural abnormalities and functional disabilities, leading to GS in families.

P1, N=68, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Mar 2025 --> May 2024

P1, N=37, Recruiting, Case Comprehensive Cancer Center | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.

Here, we used cerebellar organoids differentiated from human induced pluripotent stem cells combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences of PTCH1 mutations on human cerebellar development. Our findings demonstrate that developmental mechanisms in cerebellar organoids reflect in vivo processes of regionalisation and SHH signalling, and offer new insights into early pathophysiological events of medulloblastoma tumorigenesis without the use of animal models.

Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.

P3, N=140, Recruiting, Sol-Gel Technologies, Ltd. | Not yet recruiting --> Recruiting

Sonidegib can be considered an effective treatment option in cases where surgery or radiotherapy would be unfeasible or has previously failed, although pigmented lesions did not show complete clearance, suggesting that there are factors other than the SHH pathway involved in tumour growth. Videodermoscopy and D-OCT were useful in the quick and seamless follow-up of lesions and added valuable information in assessing efficacy.

Intriguingly, through spatial whole exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of BST resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO for not only Gorlin syndrome but sporadic BCCs as well.

P1, N=68, Active, not recruiting, St. Jude Children's Research Hospital

P2, N=44, Active, not recruiting, Endeavor Biomedicines, Inc. | Recruiting --> Active, not recruiting

P2, N=20, Not yet recruiting, Northern Sydney Local Health District

We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.

The possibility of NBCCS needs to be considered in patients with ovarian fibromas diagnosed in an early age. Skin lesions are not necessary for the diagnosis of NBCCS. Ovarian fibromas are managed with surgical excision with an attempt at preserving ovarian function. Follow-up regime and counseling on options for future fertility should be offered to patients.

Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.

P1, N=37, Recruiting, Case Comprehensive Cancer Center | Trial completion date: Nov 2023 --> May 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

Molecular analysis may help classify such tumors and show potential targetable mutations. Poster type: Poster Defense

P3, N=140, Not yet recruiting, Sol-Gel Technologies, Ltd.

Patient was further treated by vismodegib for 12 months followed by Cemiplimab. For the first time we report here that mBCC patients who were refractory to current standard of care treatments responded to taladegib with a duration of response of around one year with fewer and manageable adverse effects.

LRG patient registry enables a deeper comprehension of the disease's natural progression, encompassing treatment records and patient survival data. Further studies investigating the negative prognosis of male patients are needed to identify any factors contributing to poorer outcomes in this specific population. The median RFS time may not always be a reliable indicator to assess the effectiveness of adjuvant treatment.

The most important treatment and management are detection and resection of malignancies in the early stage, and targeted therapies have recently been used for treatment of tumors and other symptoms in these diseases. Although evidence of the effectiveness of targeted therapies has been limited, they are promising therapeutic options and further clinical trials are needed in the future.

In this study, we generated hiPSCs using peripheral blood mononuclear cells derived from the patients and healthy siblings of familial NBCCS with the novel mutation in PTCH1_c.3298_3299insAAG in the feeder- and serum-free culture conditions using SeVdp. In addition, disease-specific hiPSCs such as those expressing the PTCH1_c.3298_3299insAAG mutation could be powerful tools for revealing the genotype-phenotype relationship and pathogenicity of NBCCS.

These applied methods could not fully elucidate the genetic background of all the BCNS cases that we investigated. To uncover the missing heritability of BCNS, whole-genome sequencing or an epigenetic approach might be considered in the future.

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.

Conclusions Our study demonstrated that PTCH1 mutation could act as a potential predictor for ICIs therapy in GC. In the future, relevant prospective clinical trials need to be designed to verify this conclusion.

BCCs tend to develop after the age of 20 y, with incidence increasing dramatically with age. However, the reason why age of onset differs so substantially across symptoms in phacomatoses in general and in BCNS specifically is not yet entirely understood

With the introduction of Vismodegib and Sonidegib, two hedgehog pathway inhibitors, a response rate of 67% was observed in locally advanced disease and 38% in metastatic disease. Med. 2012;366:2171–2179

Vismodegib is one of the few therapies that has been shown to induce remission of symptoms and reduce disease burden. We present this case to raise awareness of this potential adverse event.

P1, N=37, Recruiting, Case Comprehensive Cancer Center | Active, not recruiting --> Recruiting | Trial primary completion date: Jun 2023 --> Sep 2023

"NGS can play a pivotal role in providing a definitive diagnosis and guide therapeutic efforts in central nervous system tumors."