Clinical significance of genetic profiling based on different anatomic sites in patients with mucosal melanoma who received or did not receive immune checkpoint inhibitors

Abstract

Background: To date, data on the efficacy of targeted therapies for mucosal melanoma (MM) are limited. In this study, we analyzed genetic alterations according to the primary site of origin, which could provide clues for targeted therapy for MM.

Methods: We conducted a retrospective cohort study of 112 patients with MM. Targeted sequencing was performed to analyze genetic aberrations. Kaplan-Meier analysis was conducted with the log-rank test to compare the significance among subgroups.

Results: In total, 112 patients with MM were included according to the anatomic sites: 38 (33.9%) in the head and neck, 22 (19.6%) in the genitourinary tract, 21 (18.8%) in the anorectum, 19 (17.0%) in the esophagus, 10 (8.9%) in the uvea, and 2 (1.8%) in the small bowel. The most significantly mutated genes included BRAF (17%), KIT (15%), RAS (15%), TP53 (13%), NF1 (12%), SF3B1 (11%), GNA11 (7%), GNAQ (5%), and FBXW7 (4%). A large number of chromosomal structural variants was found. The anatomic sites of esophagus and small bowel were independent risk factors for progression-free survival (PFS, hazard ratio [HR] 4.78, 95% confidence interval [CI] 2.42-9.45, P < 0.0001) and overall survival (OS, HR 5.26, 95% CI 2.51-11.03, P < 0.0001). Casitas B-lineage lymphoma (CBL) mutants showed significantly poorer PFS and OS. In contrast, MM patients who received immune checkpoint inhibitors (ICIs) had a significantly more favorable OS (HR 0.39, 95% CI 0.20-0.75, P = 0.008).

Conclusions: Our findings reveal the genetic features of patients with MM, mainly across six anatomic sites, offering a potential avenue for targeted therapies.

Keywords: Clinical significance; Genetic alterations; Mucosal melanoma; Primary site; Prognosis.

Fig. 1

Box plots showing the differences in TMB among different clinicopathological characteristics. Box plots (A-D) are shown for TMB in sample origins (P = 0.015), tumor site (B), morphology (C) and patients status (D). Significance shown as *** P < 0.001. Abbreviations: TMB, tumor mutational burden

Fig. 2

The mutational landscape of 112 patients with MM, including point mutation and SVs. From top to bottom: the total tumor mutational burden; the clinicopathological features, such as anatomic site, sex, and sample origins; the landscape of genes mutation (copy number variations, SNVs, indels, fusion gene, 5’UTR); the significantly activated pathway; the potential targeted therapy, each actionable mutation is colored by evidence level: A (NCCN guidelines and FDA guidelines), B (late trials), C (early trials), D (case report). Abbreviations: MM, mucosal melanoma; SVs, structural variants; SNVs, single nucleotide variations; UTR, untranslated regions; NCCN, national comprehensive cancer network; FDA, Food and Drug Administration

Fig. 3

Recurring mutated genes (BRAF, KIT, RAS, SF3B1, GNA11, and GNAQ) of MM in different anatomic sites. Abbreviations: MM, mucosal melanoma

Fig. 4

Kaplan–Meier survival analysis in MM. Forest plot and Kaplan–Meier survival curves for PFS (A-E) and OS (F-J) were performed for the primary tumor site, mitotic activity, CBL mutations, and with/without ICIs treatment. Significance shown as P < 0.05. Abbreviations: MM, mucosal melanoma; PFS, progression-free survival; OS, overall survival; CBL, Casitas B-lineage lymphoma; ICI, immune checkpoint inhibitor