Melanoma

This real-world study analyzed the genomic landscape of GNAQ and GNA11 mutations in 5,416 patients with metastatic solid tumors. It revealed that these mutations, while known in uveal melanoma, are also present in other cancers such as colorectal, melanoma, and gastric cancer. An immunogenic subgroup, characterized by non-hotspot mutations and high TMB or MSI, was identified and associated with potential benefit from immune checkpoint inhibitors. Canonical hotspot mutations, conversely, were predominant in TMB-low/MSS tumors. These findings highlight the importance of differentiating driver mutations from bystander mutations to guide therapeutic strategies.

A novel machine learning framework, FFixR, has been developed to address the challenges of somatic mutation detection from RNA sequencing (RNA-seq) data derived from formalin-fixed paraffin-embedded (FFPE) tissues. These tissues are prone to introducing artifacts that hinder accurate variant identification. FFixR effectively filters these artefactual mutations without requiring matched-normal samples. The tool demonstrated the ability to remove up to 98% of artifacts while maintaining good recall for true variants. This advancement enables more reliable analysis of archived FFPE samples, expanding their potential for research and clinical applications.

This retrospective study utilized targeted next-generation sequencing to identify genetic variants with prognostic value in uveal melanoma. Mutations in BAP1, CHEK2, and DICER1 were independently associated with a poorer prognosis and increased metastatic risk. Furthermore, BAP1 and LRP1B mutations were linked to epithelioid/mixed histology, while SF3B1 mutation was associated with spindle cell morphology. These findings suggest that mutational profiling could improve risk stratification and patient follow-up.

This study investigates the impact of next-generation sequencing (NGS) on the diagnosis of BAP1 inactivated melanocytic tumors (BIMTs), which often exhibit significant morphological atypia, complicating their classification. A survey among dermatopathologists revealed that incorporating NGS results significantly improved diagnostic accuracy and interobserver agreement. Specific genomic aberrations, including pathogenic variants in TERT-p, CDKN2A, PTEN, and MYC amplification, were found exclusively in malignant cases. These findings suggest that NGS could refine melanoma diagnosis, which is critical for guiding access to effective therapies.

This retrospective study evaluated the efficacy and safety of neoadjuvant immunotherapy in 24 patients with locally advanced resectable melanoma. Treatment primarily involved pembrolizumab monotherapy or a combination of ipilimumab and nivolumab. A pathological complete response (pCR) rate of 16.7% and a pathological partial response (pPR) rate of 33.3% were observed. NRAS codon 61 mutations were present in 42% of patients, with 50% of these achieving a pPR. Toxicity, particularly colitis with combination therapy, represented a significant clinical challenge.