Uveal melanoma hepatic metastases mutation spectrum analysis using targeted next-generation sequencing of 400 cancer genes

Luscan, Armelle; Just, P.-A.; Briand, Audrey; Roziers, Cyril Burin des; Goussard, P; Nitschké, Patrick; Vidaud, Michel; Avril, Marie Françoise; Terris, Benoı̂t; Pasmant, Éric

doi:10.1136/bjophthalmol-2014-305371

Cited by 32 publications

(24 citation statements)

References 22 publications

(27 reference statements)

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“…39,40 Likewise, BAP1 and SF3B1 mutations are mutually exclusive, as are EIF1AX and SF3B1 mutations, whereas TERT mutations appear to coexist specifically with GNA11 or EIF1AX mutations. 38,[41][42][43][44]…”

Section: Genetic Mutations In Uveal Melanomamentioning

confidence: 99%

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Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay

Kim

Gombos

et al. 2016

Cancer

310

258

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Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-312. V C 2016 American Cancer Society.KEYWORDS: breast cancer 1-associated protein 1 (BAP1), choroidal melanoma, diagnosis, guanine nucleotide binding protein a11 (GNA11), guanine nucleotide-binding protein Q polypeptide (GNAQ), ocular melanoma, review, science, treatment, uveal melanoma. BACKGROUND AND EPIDEMIOLOGYUveal melanoma is the most common primary intraocular malignancy. The uveal tract is the pigmented layer of the globe encompassing the iris, ciliary body, and choroid (Fig. 1). The terms choroidal melanoma and ocular melanoma are alternative terms for this cancer, because most of the uveal tract is choroidal. However, the term ocular melanoma should be avoided, because it implies the inclusion of conjunctival and adnexal melanomas, which behave and are managed like cutaneous rather than uveal primaries. Approximately 1500 new cases of uveal melanoma are diagnosed in the United States each year, most commonly arising in the choroid followed by the ciliary body. Iris melanomas are the least common location for uveal melanoma (Fig. 2).1 Although the disease has no sex preference, it is more common in middle-aged Caucasians (median age at presentation, 58 years). Risk factors include the presence of a choroidal nevus, which can be observed in 7% to 8% of the Caucasian population. Certain skin conditions, such as dysplastic nevus syndrome and nevus of Ota, are also associated with uveal melanoma.2 It has been theorized by some investigators that exposure to ultraviolet radiation increases the risk of this neoplasia, but this has not been definitively proven. Whereas certain somatic mutations are associated with neoplastic growth and distant metastasis, the malignancy is not inherited in a traditional genetic fashion, although it is believed that individuals who have germline breast cancer 1 (BRCA1)-associated protein 1 (BAP1) mutations are at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.

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Section: Genetic Mutations In Uveal Melanomamentioning

confidence: 99%

“…41 SF3B1 is reported in approximately 15% of primary uveal melanomas but has also been observed in the hepatic metastases of uveal melanoma. 43…”

Section: Sf3b1mentioning

confidence: 99%

Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay

Kim

Gombos

et al. 2016

Cancer

310

258

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“…Loss of BAP1 protein expression was frequent, and mutations in SF3B1 were rare. Most recently, Luscan et al examined five hepatic MUMs using a targeted next-generation sequencing (NGS) approach of 409 cancer genes, confirming recurrent mutations in GNAQ, GNA11, BAP1, and SF3B1, and identifying a mutation in the tumor suppressor gene FBXW7 in one of the hepatic MUMs (Luscan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Insights into genetic alterations of liver metastases from uveal melanoma

McCarthy

Kalirai

Lake

et al. 2015

Pigment Cell Melanoma Res

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The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens.

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“…The evidence from this investigation shows despite the overall appearance of global integrity found in earlier studies, there is much flexibility in the size of amplifications of 8q gain as well as the focal nature of changes affecting 8p. Uveal melanoma have recently been suggested as having a low level of mutational events in targeted cancers genes 33 and through larger scale sequencing shown to be relatively genetically stable. 34 Recent studies of cutaneous melanomas demonstrated that they can have a crisis of focal instability related to a particularly poor outcome, termed chromothripsis.…”

Section: Discussionmentioning

confidence: 99%