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Significant progress has been made in understanding the molecular pathology of uveal melanoma (UM). It is well known that genetic alterations, such as monosomy 3, polysomy 8q, and BAP1 gene-inactivating mutations, are associated with a poor prognosis in UM, whereas a gain in chromosome 6p is associated with a more favorable outcome.1 However, the pathways by which these genetic aberrations influence the processes involved in tumor dissemination and ultimate colonization are not fully understood.
In this issue of JAMA Ophthalmology, Amaro et al2 present an extensive analysis of the BTNL2 gene in UM and its association with macrophage infiltrates in these tumors. Chromosome 6p harbors the BTNL2 gene, which is a member of the butyrophilin-like B7 family of immunoregulators.3BTNL2 gene polymorphisms have been implicated in a number of diseases such as sarcoidosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and systemic lupus erythematosus. It has also been associated with prostate cancer.4 To our knowledge, the role of this gene has not yet been studied in UM. It is believed that the gene may be involved in immune surveillance as a negative T-cell regulator by decreasing T-cell proliferation and cytokine release, which would be protumor progression.3,5,6 Hence, it would seem to be contradictory to the more indolent course associated with a chromosome 6p gain in UM.
Amaro et al2 investigated the expression and missense variant frequencies of the BTNL2 gene in UM samples from patients treated in Italy and Germany, UM cell lines as well as in human macrophages (after in vitro polarization into M1 and M2 subsets) by real-time polymerase chain reaction and multiplex ligation-dependent probe amplification. They found that BTNL2 was expressed in UM specimens and UM cell lines at highly variable levels with no correlation with the amplification of chromosome 6p. It should be noted that not all of the examined UM samples were demonstrated in the Results section; the authors only analyzed those with aCGH data. Interestingly, there was also no difference seen in cell lines derived from primary or metastatic UM. The authors also demonstrated that there was no correlation between the frequencies of missense variants with UM risk. Furthermore, no association was found between racial/ethnic groups. The unexplained discrepancies noted in the allele single-nucleotide variant frequencies may have been owing to the different methods used by other investigators.
The BTNL2 gene was also expressed in both M1 and M2 macrophages, but at significantly higher levels in the latter subtype. This finding would be consistent with the immunosuppressive and tumorigenic activity associated with the M2 subtype. Chronic inflammation is a hallmark of both primary and metastatic UM (Y. Krishna, MBBS, PhD, C. McCarthy, BSc, PhD, H. Kalirai, MSc, PhD, S. E. Coupland, MBBS, PhD, unpublished data, 2016) and is thought to be a key mediator in all steps of tumorgenesis, from initiation through to progression and metastasis. The main infiltrating inflammatory cells are macrophages, particularly the M2-polarized subtype of the tumor-associated macrophages. A high density of M2 macrophages has also been reported with monosomy 3.7 It would have been of interest had the investigators confirmed that the macrophages were truly polarized into M1 and M2 in UM by immunohistochemistry (CD68 and CD163), and that greater expression of the BTNL2 gene was seen in CD163+ macrophages.
In conclusion, Amaro et al2 presented a very interesting analysis of the variable expression of the BTNL2 gene in UM that, to our knowledge, has not been previously reported. Furthermore, they demonstrate expression of this gene in M2 macrophages, which adds further novel information to the literature examining the microenvironment of UM, advocating the role of inflammation in their development and progression.
Corresponding Author: Sarah E. Coupland, MBBS, PhD, FRCPath, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, William Duncan Bldg, 6 West Derby St, Liverpool L7 8TX, United Kingdom (firstname.lastname@example.org).
Published Online: August 11, 2016. doi:10.1001/jamaophthalmol.2016.2940.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Coupland SE, Krishna Y. Genetic Variants of the BTNL2 Gene in Uveal Melanoma. JAMA Ophthalmol. 2016;134(10):1133–1134. doi:10.1001/jamaophthalmol.2016.2940
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