# Associations of Tumor Somatic Mutations and Genetic Alterations with Survival Outcomes in Melanoma Patients Treated with Ipilimumab

## TL;DR

This study explores how tumor mutations affect survival in melanoma patients treated with ipilimumab, identifying potential genomic markers for treatment response.

## Contribution

The study identifies specific tumor mutations associated with survival outcomes in melanoma patients treated with neoadjuvant ipilimumab.

## Key findings

- BRAF and NRAS mutations were detected in 73% of patients and showed mutual exclusivity and concurrence patterns.
- Mutations in several genes were linked to shorter survival outcomes, though they did not maintain significance after multiple testing correction.
- The study highlights the potential role of tumor genomic alterations in anti-tumor immunity and treatment response.

## Abstract

Background: Identifying patients most likely to benefit from immune checkpoint inhibitors (ICIs) remains a significant challenge in advanced melanoma. We evaluated the association between tumor somatic mutations and clinical outcomes, focusing on relapse-free survival (RFS) and overall survival (OS) in locoregionally advanced melanoma patients treated with neoadjuvant ipilimumab. Methods: Tumor specimens and matched peripheral blood samples from 22 patients underwent whole-exome sequencing (WES) to identify non-synonymous somatic mutations. Tumor mutational burden (TMB) was quantified, and specific mutations were analyzed for associations with survival outcomes. Results: The analysis revealed a mutational landscape dominated by single-nucleotide missense mutations with a median TMB of 11.4 mutations/MB. BRAF and NRAS mutations were detected in 73% of patients and exhibited mutual exclusivity and concurrence patterns (p < 0.05). Positional clustering identified NRAS and SLC35B4 as key contributors to melanoma (FDR p-value < 0.05). Log-rank analysis indicated that mutations in ODZ1, USP34, CEP192, EML5, KIAA1797, ATAD5, and ANKHD1–EIF4EBP were associated with shorter survival outcomes (RFS or OS). The associations remained significant in both univariate and multivariable Cox regression models adjusted for TMB. These genes can be broadly grouped into functional categories relevant to tumor progression and immune modulation. In applying multiple testing correction, none maintained statistical significance, indicating that these findings should be interpreted as exploratory and require validation in independent cohorts. Conclusions: This study identified tumor genomic alterations associated with clinical outcomes in melanoma patients treated with neoadjuvant ipilimumab, suggesting their potential role in anti-tumor immunity. These findings warrant further investigation in larger cohorts and across other ICIs in melanoma and other malignancies.