PTCH1 mutation

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.

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

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

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."

We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.

Radiation exposure by, for example, computed tomography, should be minimized as it induces new BCCs. Regular follow-up by a dermatologist for early diagnosis and treatment of (multiple) BCC's is recommended for life.

We present two patients with MHIBCC, along with a more complex cutaneous and extracutaneous phenotype. MHIBCC syndrome and BCNS may share clinical features and, indeed, both syndromes probably represent different degrees of upregulation in the Hh pathway.

Co-occurrence of medulloblastoma and cardiac fibroma is extremely rare and poses a management dilemma. Genetic counseling and antenatal screening are of utmost importance to early detect and manage patients with Gorlin-Goltz syndrome.

The results showed that the TGFBR2 had a high correlation in solid tumors with TMB and MSI. The TGFBR2 might a potential biomarker for ICIs therapy in NSCLC, and the immune microenvironment may be a factor affecting of it.

The results showed that the PTCH1 had a high correlation in solid tumors with TMB and MSI. The PTCH1 might a potential biomarker for ICIs therapy, and the immune microenvironment may be a factor affecting of it.

The patient with NSCLC and tongue cancer who exhibited objective response to EGFR-TKI, osimertinib monotherapy. The result indicates a clear response of tongue cancer to osimertinib and the potential for the use of osimertinib in tongue cancer. However, with the specific mechanism largely unknown, it is necessary to study further the effect of osimertinib on HNSCC.

Detection of the enrollment mutations in treatment arms was observed in 51.8% - 85.7% of patients tested by ctDNA with overall variant concordance between tissue and ctDNA of at least 73.6%. These findings support the use of liquid biopsy as a tool for understanding genomic profiles of cancer patients both at diagnosis and progression, less invasively than standard tissue biopsies. In addition, 7 patients were identified as MSI-H, suggesting that blood-based testing could complement tissue testing for identifying patients who may benefit from targeted therapy.

we present a patient with a new alteration in PTHC1 gene, probably associated with Gorlin´s Syndrome (because of the protein's alteration genre) and not described previously. Algorithms suggest that this variant may disrupt the consensus splice site. In addition, the patients had an excellent response to vismodegib.

This included a 2-year history of metastatic cSCC which had progressed on cemiplimab, cisplatin plus capecitabine, vismodegib (due to a germline PTCH1 mutation) and multiple courses of radiotherapy...Due to a lack of standard-of-care treatment options, the patient was enrolled on a Phase 1 clinical trial of 3-weekly intratumoral injections of an oncolytic reovirus to the supraclavicular node in combination with pembrolizumab (200mg intravenously, q3-weekly)...Therefore, in patients with advanced or metastatic cSCC who progress on anti-PD-1 therapy, addition of oncolytic virus therapy may be an effective treatment option. However, prospective studies are needed to validate the safety and efficacy of this combination compared to PD-1 inhibition alone in these patients.

Collectively, the identification of recurrent mutations in these aforementioned lesions has helped clarifying their molecular basis and to better understand the interrelationships between some tumours, but none of these genetic abnormalities is diagnostic. Since the functional effect of pathogenic mutations is context and tissue-dependent, a clear role for the reported mutations in odontogenic cysts and tumours in their pathogenesis remains to be elucidated.