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A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

ABSTRACT: Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

SUBMITTER: McDonnell KJ

PROVIDER: S-EPMC6447287 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

McDonnell Kevin J KJ Gallanis Gregory T GT Heller Kathleen A KA Melas Marilena M Idos Gregory E GE Culver Julie O JO Martin Sue-Ellen SE Peng David H DH Gruber Stephen B SB

Cancer genetics 20151222 3

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotyp ...[more]

PMID: 26774355

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Project description:AimsThe role of inflammation in conventional cutaneous melanoma has been extensively studied, whereas only little is known about the inflammatory microenvironment and immunogenic properties of spitzoid melanocytic neoplasms. The composition of infiltrating immune cells and the architectural distribution of the inflammation, in particular, are still obscure. This is the first study, to our knowledge, to systematically characterise the inflammatory patterns and the leucocyte subsets in spitzoid melanocytic lesions.Methods and resultsWe examined 79 spitzoid neoplasms including banal Spitz naevi (SN, n = 50), atypical Spitz tumours (AST, n = 17) and malignant Spitz tumours (MST, n = 12) using histopathological analysis and immunohistochemistry. Spitzoid melanocytic lesions showed a high frequency (67.1%, n = 53 of 79) of inflammation. Four inflammatory patterns were identified according to architectural composition, distribution and intensity of inflammation. The majority of the inflammatory infiltrate corresponded to CD3+ /CD8+ T lymphocytes (56.1%), followed by CD3+ /CD4+ T cells (35.7%) and CD68+ histiocytes (20.3%). CD3+ /TIA-1+ cytotoxic T lymphocytes constituted 3.7% of inflammatory cells. Rarely, CD3+ / granzyme B+ cytotoxic T lymphocytes (2.7%) and CD138+ plasma cells (0.5%) were detected in the infiltrating immune cells. There was no significant difference in the inflammatory cellular composition among the spitzoid melanocytic subgroups (SN versus AST versus MST).ConclusionOur findings demonstrate that Spitz tumours are highly immunogenic lesions. Inflammation with the presence of lymphocytic aggregates predominated in SN, but was not distinctive for this melanocytic category. A strong and intense inflammation was suggestive of an underlying malignancy. The infiltrating cytotoxic T lymphocyte subsets in Spitz tumours deserve further investigation in larger study cohorts to elucidate prognostic and immuno-oncological therapeutic relevance.

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A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

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A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

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