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Mutations in G Protein Encoding Genes and Chromosomal Alterations in Primary Leptomeningeal Melanocytic Neoplasms

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Pathology & Oncology Research

Abstract

Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal melanoma including copy number variations is unknown. Twenty primary LMNs ranging from benign and intermediate-grade melanocytomas to melanomas were tested by direct sequencing for hotspot mutations in the genes GNA11, GNAQ, BRAF, NRAS and HRAS. Furthermore, the lesions were tested for copy number variations of chromosomes frequently present in uveal melanoma (1p, 3, 6 and 8q) by multiplex ligation-dependent probe amplification (MLPA). Genome-wide analyses of copy number alterations of two leptomeningeal melanocytic neoplasms were performed using the OncoScan SNP-array. GNAQQ209 mutations were present in eleven LMNs, while two of 20 cases carried a GNA11Q209 mutation. No BRAF, HRAS or NRAS hotspot mutations were detected. Monosomy 3 and gain of 8q were present in one leptomeningeal melanoma, and one intermediate-grade melanocytoma harbored a gain of chromosome 6. With MLPA, the melanocytomas did not show any further gross chromosomal variations. Our data shows that primary LMNs, like uveal melanoma, harbor oncogenic mutations in GNAQ and GNA11 but lack mutations in BRAF, NRAS and HRAS. This finding may help in the differential diagnosis between a primary LMN and a metastasis from a cutaneous melanoma to the central nervous system. Copy number variations in some aggressive LMNs resemble those present in uveal melanoma but their prognostic significance is unclear.

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Abbreviations

LMN:

leptomeningeal melanocytic neoplasms

MC:

melanocytoma

IMC:

intermediate-grade melanocytoma

LMM:

leptomeningeal melanoma

UM:

uveal melanoma

CM:

cutaneous melanoma

CNS:

central nervous system

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Acknowledgments

We thank Sandra Hendrikx-Cornelissen and Monique Goossens for their skillful assistance with MLPA and data analysis; Roel Besseling for technical assistance with the layout of the figures, and Dr. Eugene Verwiel for general discussions and technical evaluation of the OncoScan results. We have no funding resources to declare.

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Authors and Affiliations

  1. Department of Pathology, C66, Canisius Wilhelmina Hospital, P.O. Box 9015, 6500 GS, Nijmegen, The Netherlands

    Heidi V. N. Küsters-Vandevelde & Pieter Wesseling

  2. Department of Pathology, Radboud University Medical Center, P.O. Box 9100, 6500 HB, Nijmegen, The Netherlands

    Ilse A. C. H. van Engen- van Grunsven, Jos Rijntjes, Benno Küsters, Pieter Wesseling, Willeke A. M. Blokx & Patricia J. T. A. Groenen

  3. Pathology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Daulby Street, Liverpool, L69 3GA, UK

    Sarah E. Coupland & Sarah L. Lake

  4. Department of Human Genetics, Radboud University Medical Center, P.O. Box 9100, 6500 HB, Nijmegen, The Netherlands

    Rolph Pfundt

  5. Department of Pathology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands

    Benno Küsters

  6. Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

    Pieter Wesseling

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  1. Heidi V. N. Küsters-Vandevelde
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Correspondence to Heidi V. N. Küsters-Vandevelde.

Electronic supplementary material

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ESM 1

(DOC 37 kb)

Online Resource 1. Primers used for mutational analysis (DOC 41 kb)

Online Resource 2. MLPA data analysis (DOC 32 kb)

Fig5

Online Resource 3. CNV plot and allelic frequency plot obtained by OncoScan SNP-analysis for patient #14 (IMC) 20 (GIF 130 kb)

High Resolution Image (TIFF 7040 kb)

Fig6

Online Resource 4. CNV plot and allelic frequency plot obtained by OncoScan SNP-analysis for patient #18 (LMM) (GIF 139 kb)

High Resolution Image (TIFF 7071 kb)

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Küsters-Vandevelde, H.V.N., van Engen- van Grunsven, I.A.C.H., Coupland, S.E. et al. Mutations in G Protein Encoding Genes and Chromosomal Alterations in Primary Leptomeningeal Melanocytic Neoplasms. Pathol. Oncol. Res. 21, 439–447 (2015). https://doi.org/10.1007/s12253-014-9841-3

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