Role of somatic mutations and chromosomal aberrations in the prognosis of uveal melanoma in a Spanish patient cohort

Abstract

Background Uveal melanoma (UM) has a high tendency to cause liver metastases. Metastatic disease is fatal, with a low survival rate. There are two large groups of UMs that, according to their risk of metastatic disease, can be divided into risk subgroups based on histopathological, cytogenetic and molecular characteristics. The presence of somatic mutations in certain genes may explain the origin and prognosis of these tumours. Methods Forty‐six UM samples previously classified as high or low metastatic risk according to chromosome 3 copy number status were tested for somatic mutations. A multi‐gene targeting strategy was adopted, and sequencing was performed using AmpliSeq technology. Results Mutations were found in all major UM‐related genes. BAP1 mutations confer an increased risk of metastases in high‐risk tumours; thus, this gene acts as a strong prognostic predictor in UM. The presence of somatic mutations in LZTS1 did not show significant differences in the risk of metastases. Conclusions This result supports the idea that exploring mutations and copy number variations in UM provides insights into patient outcomes. Genetic tests allow the determination of accurate personalized molecular profiles with a fundamental prognostic purpose.

Molecular profiling of primary uveal melanoma: results of a Polish cohort

“…In our study, we found a statistically significant association between the presence of GNA11 mutation and longer PFS (P = 0.0317); however, our sample size is small. [4,24,25,28,32,33,40]. In our study group, we did not detect an association between GNAQ mutations and survival.…”

“…UM often harbor mutations affecting GNAQ (34-58%), GNA11 (21-59%), PLCB4 (0-3%), or CYSLTR2 (0-6%), initiating mutations that are members of the G-protein alpha q signaling cascade; and BAP1 (35-91%), SF3B1 (16-37%), and EIF1AX (0-13%), progression mutations (Table 3) [3,4,8,[14][15][16][17][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. In our cohort, the frequency of GNAQ, GNA11, PLCB4, carcinogenesis initiating genes, was similar to those of published literature (Table 3).…”

GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma

“…The frequency of GNAQ/GNA11 mutations is approximately 80-90% of the UM cases [18,20,21]. In the scientific literature, the frequencies of GNAQ mutations have been reported to range from 24.2 to 53.3% and those of GNA11 mutations from 24.2 to 60% [20,[28][29][30][31]. In previous studies, non-Caucasian populations have shown reduced mutation frequencies in these two genes, but more recent studies have shown that mutations in this population may be closer to the frequencies previously mentioned [32,33].…”

“…Contrastingly, in the GNAQ gene, a one-base change at codon 209 (CAA) can predict the substitution of glutamine by leucine (A > T, p.Q209L) and proline (A > C, p.Q209P), in most cases [17,28]. In exon 5, other mutations, including p.Q209M, p.Q209H, p.Q209I, p.F228L, and p.M203V in GNAQ and p.Q209Y, p.E234K, p.E221D in GNA11, have also been described [28,30] (Table 1). Overall, the frequency of mutations in the exon 4 of GNAQ and GNA11 genes is lower.…”

Scientific and clinical implications of genetic and cellular heterogeneity in uveal melanoma

“…For UM however, this is less evident. Recurrent mutations in BAP1, SF3B1 and EIF1AX, have been found in UM but none are as common as the presence of GNAQ/11 [35][36][37][38][39][40][41][42][43][44]. This shows that there are multiple second hits possible, allowing the tumour to divert into different directions and become (intertumorally) heterogeneous with distinct clinical and pathological behaviour.…”