Final Diagnosis -- Molecular Testing of a Metastatic Subcutaneous Lesion

FINAL DIAGNOSIS

Genomic Alterations Identified:

DNA Mutations and Gene Fusions

• GNA11 mutation p.Q209L
• BAP1 mutation p.P329Rfs*63

Copy Number Alterations

• 8q (NBN and MYC) copy number GAIN
• 8p (FGFR1) copy number suspected LOSS
• 6q (ESR1, and ROS1) copy number suspected LOSS

DISCUSSION

Uveal melanoma arises from intraocular melanocytes and, while rare, it is the most common intraocular melanocytic tumor. Unlike most cutaneous melanomas, uveal melanomas have unique driver mutations (GNAQ or GNA11) and its mutational profile could be categorized to correlate with clinical outcomes. Significant genetic mutations include activating driver mutations in GNAQ or GNA11 genes followed by acquisition of BAP1 loss of function mutations or EIF1AX or SF3B1 activating mutations along with chromosomal alterations including losses of chromosome 1p, 6q, 8p, and 16q, as well as gains in 6p and 8q regions. Unlike cutaneous melanomas, uveal melanomas have a low tumor mutation burden and do not carry the ultra-violet ray mutational (C>T or CC>TT) signature.

Activating GNAQ and GNA11 mutations are mutually exclusive, involve codons 183 and 209 and found in virtually all uveal melanomas. They each encode different subunits of G-protein couple receptors ultimately involved in cell proliferation. Additional significant mutations occur in BAP1, SF3B1 and EIF1AX gene and are usually exclusive among them.

BAP1 alterations are seen in about 85% of uveal melanomas and portent a poor prognosis. BAP1 is a nuclear ubiquitin hydrolase and tumor suppressor gene, involved in cell proliferation chromatin regulation, and DNA repair. Phenotypic evidence of a BAP1 alteration was noted in this case, as BAP1 immunohistochemical protein expression was lost. High allelic frequency (81%) of BAP1 mutation compared to GNA11 mutation (43%) is due to chromosome 3p loss resulting in deletion of wild type BAP1 allele that resides within it.

Comprehensive analysis on uveal melanoma has identified four molecular distinct and clinically relevant subgroups based on the combination of DNA mutational profile and copy number alterations. Please see Figure 1.

REFERENCES

1. Royer-Bertrand, et al. Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing. Am J Hum Genet. 2016 Nov 3; 99(5): 1190-1198.
2. Gordon Robertson, A, et al. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell. 2017 Aug 14; 32(2): 204-220.e15.
3. Murali R, et al. Tumours associated with BAP1 mutations. Pathology 2013;45(116-26):2.
4. Cheung M, et al. Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma. Cancer Genet. 2013;206(206-10):5
5. Sacco JJ, et al. Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors. Oncotarget 2015;6(13757-71):15.
6. Chen X, et al. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene 2014;33(4724-34):39

Contributed by Laura Favazza, DO and Arivarasan Karunamurthy, MD