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SLURP‐1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene
Author(s) -
Bergqvist Christina,
Kadara Humam,
Hamie Lamiaa,
Nemer Georges,
Safi Remi,
Karouni Mirna,
Marrouche Nadine,
Abbas Ossama,
Hasbani Divina J.,
Kibbi Abdul G.,
Nassar Dany,
Shimomura Yutaka,
Kurban Mazen
Publication year - 2018
Publication title -
international journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 93
eISSN - 1365-4632
pISSN - 0011-9059
DOI - 10.1111/ijd.13850
Subject(s) - melanoma , pathology , medicine , immunohistochemistry , lineage (genetic) , genodermatosis , skin cancer , palmoplantar keratoderma , mutation , gene , cancer research , biology , hyperkeratosis , cancer , genetics
Background Mal de Meleda ( MDM ) is a rare inherited autosomal recessive genodermatosis characterized by palmoplantar keratoderma ( PPK ) with transgrediens and caused by mutations in the SLURP 1 gene. Uncommonly, cutaneous tumors have been found at PPK sites in MDM patients. Objective To study a Middle Eastern family with MDM with both PPK and skin tumors. Methods We studied a Middle Eastern (Palestinian) family with clinical features of MDM and cutaneous tumors. Histopathological analysis was performed on biopsies from skin lesions found in the affected individuals. Direct sequencing of SLURP 1 was performed in MDM affected members. In silico analysis of publicly available datasets was used to survey SLURP 1 mRNA levels in normal and malignant tissues. Statistical analysis was performed in the R statistical language. Results Affected members from the Middle Eastern family displayed severe forms of PPK consistent with MDM . Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas ( SCC s) and melanoma. Sequence analysis revealed homozygous SLURP 1 mutations (c.82delT) in the affected members. Following analysis of various publicly available expression datasets, SLURP 1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts. There was significant decrease in SLURP ‐1 expression in melanomas versus melanocytic nevi as well as a highly significant decrease in SLURP ‐1 expression in metastatic melanomas as compared to primary melanoma. Conclusion Our study underscores cases of Middle Eastern MDM with SLURP 1 mutations and skin malignancies at PPK sites. Our findings also highlight a plausible epithelial lineage‐specific tumor suppressor role for the SLURP 1 gene, as well as a role in the development and metastasis of melanoma and thus a potential molecular signature for melanoma.