Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

Abstract

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

Driver Mutations in Uveal Melanoma

“…With multiple groups reporting their whole-exome sequencing results for UM, rare mutations in other genes have been found and will likely continue to be discovered. 11,16,23 The importance of these additional infrequent events will need to be assessed in future studies. A fourth limitation was the retrospective design and its effect on the clinical outcomes obtained.…”

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

“…Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4]. Compared with cutaneous melanoma, uveal melanoma is characterized by its distinct genetic profile and clinical presentation, where most metastases are detected in the liver [5][6][7][8][9][10]. Once uveal melanoma metastasizes, prognosis is poor because metastatic uveal melanoma (MUM) tends to be widespread within the liver and only surgically resectable in some cases [11,12].…”

Twelve-year survival and immune correlates in dendritic cell–vaccinated melanoma patients

“…Cancer vaccines aim at inducing or restimulating tumor-specific T cell responses. Based on preclinical (1)(2)(3)(4)(5)(6)(7)(8)(9) and initial clinical reports (10)(11)(12), they could be instrumental in breaking primary resistance to checkpoint blockade of tumors with low mutational load (13)(14)(15) and in increasing response rates of highly mutated tumors, such as melanoma (11).…”