High-frequency mutations seen in conjunctival melanoma

Patients with conjunctival melanoma exhibit a high frequency of BRAF and NRAS mutations, as well as ATRX and NF1 mutations, reports a study.

Additionally, an NRAS mutation is indicative of a higher risk for metastasis and death, while loss of ATRX and alternative lengthening of telomeres (ALT) suggests early events in conjunctival melanoma development.

In this observational case series, researchers assessed targetable mutations and molecular genetic pathways in patients with conjunctival melanoma. They recorded the mutational profile of the tumour by next-generation sequencing (NGS), ALT by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry at 2 and 5 years of tumour-related metastasis and death.

One hundred one patients (mean age 60 years, 52 percent male, 88 percent White) were included. The NGS panels initially targeted BRAF only (n=6, 6 percent), BRAF/NRAS (n=17, 17 percent), and BRAF/NRAS/NF1 (n=10, 10 percent). The expanded 592-gene panel was used to test 68 tumours.

NGS identified high-frequency mutations in NF1 (29/74, 39 percent), BRAF (31/101, 31 percent), NRAS (25/95, 26 percent), and ATRX (17/68, 25 percent). Twelve (71 percent) of those with an ATRX mutation had an additional NF1 mutation.

In a subset analysis of 21 melanomas, ATRX mutation correlated with loss of ATRX protein expression and ALT. Loss of ATRX mutation and ALT were found in both intraepithelial and invasive tumours, suggesting that an ATRX mutation is indicative of conjunctival melanoma progression.

The NF1 and ATRX mutations correlated with tarsal (vs nontarsal) tumours (NF1: 28 percent vs 9 percent; p=0.035; ATRX: 41 percent vs 14 percent; p=0.021) and orbital (vs nonorbital) tumours (ATRX: 24 percent vs 2 percent; p=0.007).

Furthermore, ATRX^MUT (vs ATRX^WT) tumours correlated with a lower 2-year rate of metastasis (0 percent vs 24 percent; p=0.005), while NRAS^MUT (vs NRAS^WT) tumours correlated with a higher 2-year rate of metastasis (28 percent vs 14 percent; p=0.07) and death (16 percent vs 4 percent; p=0.04), with a fivefold increased risk of death (relative risk, 5.45, 95 percent confidence interval, 1.11–26.71; p=0.039).