Sinead Toomey

IJMS is retracting the article titled “Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)”

Small Cell Carcinoma of the Ovary (SCCO) is an extremely rare form of ovarian cancer characterised by bi-allelic mutations in the SMARCA4 gene, a member of the SWI/SNF chromatin remodelling complex. Most previous analyses have characterised SCCO using whole exome sequencing; we present the treatment plans of two SCCO patients with post-treatment analysis of whole genome sequencing and tumour RNA sequencing which include structural variant and mutational signature analysis not previously reported in the literature for this cancer type. Both patients underwent salpingo-oophorectomy followed by BEP chemotherapy and pelvic radiotherapy leading to 34 month remission in one case though one patient died 12 months post-diagnosis. Consistent with known aetiology, we identified complete SMARCA4 loss of function and probable SMARCA2 expression loss in both patients. Beyond this, both tumours present remarkably low tumour mutational burdens and were microsatellite stable though one sample also showed chromosomal instability with high levels of inversions and a ploidy level of 2.8 which has not been well characterised in SCCO patients. This report contributes towards the small number of cases of SCCO that are currently documented and have their genome characterised in the literature.

Congenital lipomatous overgrowth, vascular epidermal nevi, and skeletal abnormalities (CLOVES) syndrome is a rare genetic disorder caused by somatic activating mutations in the PIK3CA gene that arise during embryonic development. Mutations in the PI3K–AKT–mTOR pathway have been linked to various benign overgrowth disorders, including syndromes within the PIK3CA -related overgrowth spectrum. Somatic PIK3CA mutations also occur frequently across many cancer types; however, evidence linking CLOVES syndrome to increased cancer risk is not conclusive. Here, we describe a whole-genome sequencing (WGS) study of a primary pT3 high-grade urothelial carcinoma in a 62-year-old male patient diagnosed with CLOVES syndrome. A left laparoscopic nephroureterectomy was completed. Tumour tissue and a matched blood sample were collected for whole-genome sequencing, and somatic variant detection was performed. The somatic alterations were consistent with previous reports of urothelial carcinoma, including homozygous deletions of CDKN2A and CDKN2B . In this case, we could not detect somatic PIK3CA alterations in this patient’s urothelial carcinoma and suggest that it is unrelated to CLOVES syndrome.

Tight junction (TJ) proteins, such as Junctional Adhesion Molecule-A (JAM-A), claudins, and occludin, play increasingly recognized roles in cancer biology beyond their structural functions, influencing tumour proliferation, invasion, metastasis and therapy resistance. Understanding how these proteins modulate tumour progression in vivo requires models that are both physiologically relevant and ethically viable. The chick chorioallantoic membrane (CAM) xenograft model has emerged as a powerful and cost-effective in vivo system that aligns with the 3Rs (replacement, reduction, and refinement), offering unique advantages such as vascular accessibility, rapid tumour growth kinetics and immunotolerance. This review explores how the CAM model can be leveraged to study the mechanistic role of TJ proteins in tumour–stroma interactions, angiogenesis, extracellular matrix (ECM) remodelling and mechanotransduction, including the YAP/TAZ pathway. While limitations remain, particularly with respect to immune modelling and long-term studies, recent advances in imaging, genetic manipulation and integration of patient-derived xenografts (PDXs) are expanding the model’s translational relevance. Standardizing methodologies and embracing new molecular tools will further elevate the utility of this approach as a complementary platform to traditional rodent models, with significant promise for TJ-focused cancer research and therapeutic innovation.

Tight junction (TJ) proteins such as Junctional Adhesion Molecule-A (JAM-A), claudins, and occludin play increasingly recognised roles in cancer biology beyond their structural functions, influencing tumour proliferation, invasion, metastasis and therapy resistance. Understanding how these proteins modulate tumour progression in vivo requires models that are both physiologically relevant and ethically viable. The Chick Chorioallantoic Membrane (CAM) Xenograft model has emerged as a powerful and cost-effective in vivo system that aligns with the 3Rs (Replacement, Reduction, and Refinement), offering unique advantages such as vascular accessibility, rapid tumour growth kinetics and im-munotolerance. This review explores how the CAM model can be leveraged to study the mechanistic role of TJ proteins in tumour-stroma interactions, angiogenesis, extracellular matrix (ECM) remodelling and mechanotransduction, including the YAP/TAZ pathway. While limitations remain, particularly with respect to immune modelling and long-term studies, recent advances in imaging, genetic manipulation and integration of pa-tient-derived xenografts (PDXs) are expanding the model’s translational relevance. Standardising methodologies and embracing new molecular tools will further elevate the utility of this approach as a complementary platform to traditional rodent models, with significant promise for TJ-focused cancer research and therapeutic innovation.

Metastatic meningioma is rare, occurring in less than 1% of patients, and very few case studies have been reported, in particular for those that have spread to the lungs. Here we describe a rare case of metastatic meningioma to the lungs. Following a discussion at a medical oncology multi-disciplinary team meeting, whole genome sequencing was requested in November 2021 and discussed at a neurosurgical molecular tumor board in June 2022. Sequencing was performed on matched longitudinal collected samples of the primary tumor resection, the re-excised recurrent tumor after adjuvant radiation therapy, the lung metastases before treatment with sunitinib, and one paired blood sample for tumor-normal analysis. Whole genome characterization and clonal evolution analysis confirmed neurofibromatosis 2 (NF2) gene loss as the main driver of this cancer. In the same cancer clone as NF2, we identified a BRCA2 (p.E51K) mutation was present in all tumors, which may represent a potential driver event, though evidence supporting this is currently limited. Although this mutation is predicted to potentially influence homologous recombination, its clinical relevance as a biomarker for PARP inhibition remains speculative and requires further investigation. We also noted a SETD2 (p.S1885N) mutation that was present only in the recurrent tumor which was identified as a predicted biomarker of response to WEE1 inhibition. There was a stepwise increase in tumor mutational burden (TMB) from the primary meningioma to lung metastases, suggesting this patient may have been a candidate for immunotherapy.

The CDK4/6 inhibitor Ribociclib has shown limited efficacy as a monotherapy in colorectal cancer (CRC). However, combining Ribociclib with targeted therapies could present a viable strategy for treating CRC. This study evaluated the combination of Ribociclib and the PI3K inhibitor Alpelisib across four distinct cell lines representing different mutational statuses (PIK3CA/KRAS wild-type, KRAS-mutated, PIK3CA-mutated, and PIK3CA/KRAS-mutated). We analyzed the drugs’ impact on key proteins involved in the PI3K pathway, cell cycle regulation, and apoptosis. The combination of Alpelisib and Ribociclib demonstrated a synergistic anti-proliferative effect across all cell lines, leading to a simultaneous decrease in pRB, pAKT, and p-S6 levels, and a more comprehensive suppression of the PI3K/AKT/mTOR pathway. Additionally, there was an upregulation of the apoptotic marker, p-BCL2, in cells treated with the combination compared to controls. In vivo studies using Caco-2, LS1034, and SNUC4 xenografts revealed a significant reduction in tumour growth with the combination therapy compared to single-agent treatments. These findings suggest that combining Alpelisib and Ribociclib could be a promising therapeutic approach for CRC, warranting further clinical exploration.

Up to 15% of lung cancer patients present two or more anatomically separate primary lung lesions, known as multiple primary lung cancers (MPLCs). While surgical resection or stereotactic body radiation therapy (SBRT) is the standard of care for most early-stage lung cancer cases, this may not be an option for patients with widespread tumours, highlighting the need for the improved targeted management of MPLC patients, which remains challenging. Moreover, the spontaneous regression (SR) of small-cell lung cancer (SCLC) is rare, with only four cases accounted for between 1988 and 2018. We report a rare MPLC case harbouring the mixed histology of non-small-cell lung cancer adenocarcinoma (NSCLCa) and SCLC and the SR of SCLC without treatment. The patient was diagnosed in 2015 with MPLCs, identified as NSCLCa and SCLC. In 2016, a restaging PET/CT scan prior to the start of treatment showed SCLC SR. In 2018, a further tumour was detected in the patient’s mandible, and a re-biopsy of the SCLC revealed histology consistent with NSCLCa. Whole-genome sequencing (WGS) analysis identified a high expression of programmed death ligand-1 (PDL-1) in the NSCLCa, which was treated with pembrolizumab. WGS revealed distinct genomic profiles and mutational mechanisms in MPLCs, suggesting the need for distinct targeted therapies to improve the management of MPLC patients and highlighting the importance of precision evaluation.

HER2-positive (HER2+) breast cancer accounts for 20–25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10–05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients. Here we report predictive modelling of neoadjuvant therapy response using clinicopathological and genomic features of pre-treatment tumour biopsies identified age, estrogen receptor (ER) status and level of immune cell infiltration may together be important for predicting response. Clonal evolution analysis of longitudinally collected tumour samples show subclonal diversity and dynamics are evident with potential therapy resistant subclones detected. The sources of greater pre-treatment immunogenicity associated with a pathological complete response is largely unexplored in HER2+ tumours. However, here we point to the possibility of APOBEC associated mutagenesis, specifically in the ER-neg/HER2+ subtype as a potential mediator of this immunogenic phenotype.