ABSTRACT
Although the pathogenesis of solar lentigo (SL) involves chronic ultraviolet (UV) exposure, cellular senescence, and upregulated melanogenesis, underlying molecular-level mechanisms associated with SL remain unclear. The aim of this study was to investigate the gene regulatory mechanisms intimately linked to inflammation in SL. Skin samples from patients with SL with or without histological inflammatory features were obtained. RNA-seq data from the samples were analyzed via multiple analysis approaches, including exploration of core inflammatory gene alterations, identifying functional pathways at both transcription and protein levels, comparison of inflammatory module (gene clusters) activation levels, and analyzing correlations between modules. These analyses disclosed specific core genes implicated in oxidative stress, especially the upregulation of nuclear factor kappa B in the inflammatory SLs, while genes associated with protective mechanisms, such as SLC6A9, were highly expressed in the non-inflammatory SLs. For inflammatory modules, Extracellular Immunity and Mitochondrial Innate Immunity were exclusively upregulated in the inflammatory SL. Analysis of protein-protein interactions revealed the significance of CXCR3 upregulation in the pathogenesis of inflammatory SL. In conclusion, the upregulation of stress response-associated genes and inflammatory pathways in response to UV-induced oxidative stress implies their involvement in the pathogenesis of inflammatory SL.
Subject(s)
Lentigo , Multigene Family , Humans , Inflammation/genetics , Cellular Senescence , Immunity, Innate , Lentigo/geneticsSubject(s)
East Asian People , Lentigo , Humans , Lentigo/genetics , Mutation , Phenotype , Tumor Suppressor Proteins , Male , Child, Preschool , ChildABSTRACT
Lentigines are well-defined, small, brown macules resulting from the accumulation of melanin content in the basement membrane zone with an increase in the number of melanocytes. Hereditary multiple lentigines (ML) can be associated with multiple genes and are not commonly encountered in clinical practice. Patients can solely have skin involvement or present with multisystemic deformative phenotypes. This study aimed to describe four unrelated Chinese families presenting with ML as their first visit symptom. We performed whole-exome sequencing (WES) and Sanger sequencing on all patients and immediate family members for precise molecular diagnosis. Two novel variants c.1548 T > A (p.Ser516Arg) and c.1811C > A (p.Thr604Lys) in SASH1, and two recurrent variants c.1403C > T (p.Thr468Met) and c.1493G > T (p.Arg498Leu) in PTPN11, were identified in these four families. We also summarized the genes associated with ML and differential diagnosis of pigment abnormality. We suggested that the molecular diagnosis of ML should be emphasized because it can help in the clinical differential diagnosis and further genetic counseling and prognosis.
Subject(s)
East Asian People , Lentigo , Humans , Lentigo/diagnosis , Lentigo/genetics , Melanocytes , Mutation , Phenotype , SyndromeABSTRACT
Solar lentigines (SLs) are a hallmark of human skin aging. They result from chronic exposure to sunlight and other environmental stressors. Recent studies also imply genetic factors, but findings are partially conflicting and lack of replication. Through a multi-trait based analysis strategy, we discovered that genetic variants in telomerase reverse transcriptase were significantly associated with non-facial SL in two East Asian (Taizhou longitudinal cohort, n = 2,964 and National Survey of Physical Traits, n = 2,954) and one Caucasian population (SALIA, n = 462), top SNP rs2853672 (P-value for Taizhou longitudinal cohort = 1.32 × 10â28 and P-value for National Survey of Physical Traits = 3.66 × 10â17 and P-value for SALIA = 0.0007 and Pmeta = 4.93 × 10â44). The same variants were nominally associated with facial SL but not with other skin aging or skin pigmentation traits. The SL-enhanced allele/haplotype upregulated the transcription of the telomerase reverse transcriptase gene. Of note, well-known telomerase reverse transcriptaseârelated aging markers such as leukocyte telomere length and intrinsic epigenetic age acceleration were not associated with SL. Our results indicate a previously unrecognized role of telomerase reverse transcriptase in skin agingârelated lentigines formation.
Subject(s)
Lentigo , Photosensitivity Disorders , Telomerase , Humans , Telomerase/genetics , Telomerase/metabolism , Lentigo/genetics , Lentigo/epidemiology , Aging , Skin/metabolism , Telomere/metabolismABSTRACT
SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun-exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun-exposed areas, using next-generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression.
Subject(s)
Lentigo/pathology , Mutation, Missense , Phenotype , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Child, Preschool , Female , Humans , Lentigo/genetics , Male , Pedigree , PrognosisABSTRACT
Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.
Subject(s)
Autophagy/physiology , Cell Differentiation/physiology , Epidermis/physiology , Skin Aging/physiology , Skin Pigmentation/physiology , Skin/physiopathology , Adult , Aging, Premature/metabolism , Aging, Premature/physiopathology , Autophagy/genetics , Cell Differentiation/genetics , Cell Line , Epidermis/metabolism , Female , Gene Expression Regulation , Humans , Keratinocytes/cytology , Keratinocytes/physiology , Lentigo/genetics , Lentigo/metabolism , Lentigo/physiopathology , Male , Middle Aged , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , S-Phase Kinase-Associated Proteins/genetics , S-Phase Kinase-Associated Proteins/metabolism , Skin/metabolism , Skin Aging/genetics , Skin Pigmentation/geneticsSubject(s)
Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Stromal Tumors/diagnosis , Lentigo/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Chemotherapy, Adjuvant , DNA Mutational Analysis , Dermoscopy , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Female , Gastrectomy , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/therapy , Gastrointestinal Stromal Tumors/complications , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/therapy , Gastroscopy , Humans , Imatinib Mesylate/therapeutic use , Lentigo/therapy , Middle Aged , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Point Mutation , Proto-Oncogene Proteins c-kit/genetics , Skin/diagnostic imaging , Stomach/diagnostic imaging , Stomach/pathology , Treatment OutcomeSubject(s)
Cafe-au-Lait Spots/genetics , Lentigo/genetics , Mutation , PAX3 Transcription Factor/genetics , Phenotype , Adult , Cafe-au-Lait Spots/pathology , Child , Female , Heterozygote , Humans , Lentigo/pathology , Male , Skin/pathologyABSTRACT
Although lentigines are usually benign, they can be associated with a number of genetic syndromes in which neoplasms and other multi-system pathological processes occur. Here, we report the case of a 6-year-old girl who presented with atypical lentiginosis and hyperpigmentation caused by a de novo genetic variant in the KIT gene.
Subject(s)
Lentigo/genetics , Mutation, Missense , Proto-Oncogene Proteins c-kit/genetics , Child , Female , Humans , Exome SequencingABSTRACT
Solitary congenital or early apparent pigmented macules are usually without relevance; however, when multiple, extensive or in a patterned arrangement, they are not uncommonly the first sign of an underlying genetic syndrome. The present article gives an overview on the clinical significance of multiple café-au-lait macules, multiple lentigines and pigmentary mosaicism and discusses the differential diagnosis of associated syndromes. Early diagnosis with the essential contribution of the dermatologist is not only important for genetic counseling but can also contribute to avoidance of sometimes life-threatening complications.
Subject(s)
Cafe-au-Lait Spots , Hyperpigmentation , Lentigo , Skin Abnormalities/genetics , Cafe-au-Lait Spots/diagnosis , Cafe-au-Lait Spots/genetics , Diagnosis, Differential , Genetic Counseling , Genetic Diseases, Inborn , Humans , Hyperpigmentation/diagnosis , Hyperpigmentation/genetics , Lentigo/genetics , Lentigo/pathology , Mosaicism , SyndromeABSTRACT
Wnt/ß-catenin signalling promotes melanogenesis in melanocytes and also induces melanocytogenesis from melanocyte stem cells (McSCs). Previous study reported that WNT1, a ligand which activates Wnt/ß-catenin signalling pathway, was more highly expressed in the epidermis at SLs than in normal skin areas, suggesting that WNT1 causes hyperpigmentation. To elucidate the mechanism by which WNT1 expression is increased in SLs, we examined the methylation of 5-carbon of cytosine (5mC), that is 5-methylcytosine (5mC) level, in a region within the WNT1 promoter; the methylation of the region was known to negatively regulate WNT1 gene expression. We used an immortalized cell line of human interfollicular epidermal stem cells to analyse the effect of UVB irradiation on DNA methylation level of WNT1 promoter and found that UVB irradiation caused demethylation of WNT1 promoter and promoted WNT1 mRNA expression. It was also found that UVB irradiation reduced the expression of DNA methyltransferase 1 (DNMT1), an enzyme responsible for maintaining methylation patterns during cell division. Pathological analysis of SLs and non-SL regions in the human skin revealed that both DNMT1 expression and 5mC level were decreased at SLs compared to non-SL skins. Furthermore, bisulphite sequencing showed that the methylated CpG level in WNT1 promoter was also lower at SLs than in non-SL skins. Thus, in the skin exposed to a high amount of UV rays, excessive expression of WNT1 is thought to be caused by the demethylation of WNT1 promoter, and the upregulated WNT1 promotes melanocytogenesis and melanogenesis, then resulting in SL formation.
Subject(s)
DNA Methylation , Lentigo/etiology , Lentigo/genetics , Ultraviolet Rays/adverse effects , Wnt1 Protein/genetics , Aged , Biopsy , Cell Line , CpG Islands , DNA (Cytosine-5-)-Methyltransferase 1/genetics , Epidermal Cells , Female , Humans , Hypopigmentation/metabolism , Keratinocytes/metabolism , Male , Melanocytes/metabolism , Middle Aged , RNA, Small Interfering/metabolism , Signal Transduction , Skin/metabolismABSTRACT
BACKGROUND: Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia. OBJECTIVE: To characterize the clinicopathologic features of these rare lesions. METHODS: Subungual atypical lentiginous melanocytic proliferations from patients <20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible. RESULTS: Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome. LIMITATIONS: Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only. CONCLUSION: Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.
Subject(s)
Lentigo/pathology , Melanocytes/pathology , Nail Diseases/pathology , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Hutchinson's Melanotic Freckle/diagnosis , Hutchinson's Melanotic Freckle/genetics , Hutchinson's Melanotic Freckle/pathology , Hutchinson's Melanotic Freckle/surgery , In Situ Hybridization, Fluorescence , Lentigo/diagnosis , Lentigo/genetics , Lentigo/surgery , Male , Melanoma/diagnosis , Melanoma/genetics , Melanoma/pathology , Melanoma/surgery , Nail Diseases/diagnosis , Nail Diseases/genetics , Nail Diseases/surgery , Retrospective Studies , Sensitivity and Specificity , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Young AdultABSTRACT
Carney complex is a multiple neoplasia syndrome having endocrine and non-endocrine manifestations. Diagnostic criteria include myxoma, lentigines, and primary pigmented nodular adrenocortical disease, amongst other signs/symptoms. In most cases it is an autosomal dominant disease, and diagnosis therefore requires study and follow-up of the family members. Inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 other disease-related genes, including PRKACA and PRKACB activating mutations, have also been related with Carney complex. This review will address the genetic aspects related to Carney complex.
Subject(s)
Carney Complex/genetics , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics , Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics , Neoplastic Syndromes, Hereditary/genetics , Carney Complex/metabolism , Cushing Syndrome/etiology , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism , Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Female , GTP-Binding Proteins/metabolism , Genetic Heterogeneity , Humans , Lentigo/genetics , Male , Multiprotein Complexes/metabolism , Neoplastic Syndromes, Hereditary/metabolism , Signal Transduction , Transcription, GeneticABSTRACT
BACKGROUND: Actinic lentigos (AL) are benign hyperpigmented skin lesions associated with photoageing. Despite their high prevalence, biological mechanisms driving their formation remain unclear. OBJECTIVES: To provide new insights about the physiopathology of AL through a comprehensive description of their histological and molecular features. METHODS: Quantitative analysis of dermoscopic images was used to select AL containing elongated patterns, predicted to display a highly deformed dermal-epidermal junction (DEJ), on the back of the hands of 15 Caucasian women. Biopsies from lesional and adjacent nonlesional (NL) areas were processed for histological analysis or gene expression profiling. RESULTS: Histological staining confirmed a drastic deformation of the DEJ in AL, with deep epidermal invaginations into the dermis. Although the melanin content was significantly higher in AL compared with NL epidermis, the distribution of melanocytes along the DEJ was unchanged. Transcriptomic analysis revealed a signature of 529 genes differently expressed in AL vs. NL skin. Alteration of epidermal homeostasis was confirmed by the dysregulation of keratinocyte proliferation and differentiation markers. Surprisingly, canonical genes involved in melanogenesis were not significantly modulated in AL. A striking finding was the overexpression of a large group of genes involved in dermal extracellular matrix organization and remodelling. Dermal alterations were confirmed by immunolabellings on AL and NL sections. CONCLUSIONS: Drastic disorganization of the cutaneous structure in AL is accompanied by a specific molecular signature revealing alterations in both epidermal and dermal compartments. In particular, our results suggest that local modifications of the dermal extracellular matrix might contribute to hyperpigmentation in AL.
Subject(s)
Extracellular Matrix/pathology , Lentigo/pathology , Photosensitivity Disorders/pathology , Skin/pathology , Aged , Back , Dermoscopy , Epidermis/metabolism , Extracellular Matrix/metabolism , Female , Gene Expression Profiling , Genes/genetics , Hand Dermatoses/genetics , Hand Dermatoses/metabolism , Hand Dermatoses/pathology , Humans , Lentigo/genetics , Melanins/metabolism , Melanocytes/metabolism , Middle Aged , Photosensitivity Disorders/genetics , Skin/metabolism , Transcriptome/genetics , Up-Regulation/geneticsABSTRACT
Sunlight exposure induces signalling pathways leading to the activation of melanin synthesis and tanning response. MicroRNAs (miRNAs) can regulate the expression of genes involved in pigmentation pathways by binding to the complementary sequence in their 3'untranslated regions (3'UTRs). Therefore, 3'UTR SNPs are predicted to modify the ability of miRNAs to target genes, resulting in differential gene expression. In this study, we investigated the role in pigmentation and sun-sensitivity traits, as well as in melanoma susceptibility, of 38 different 3'UTR SNPs from 38 pigmentation-related genes. A total of 869 individuals of Spanish origin (526 melanoma cases and 343 controls) were analysed. The association of genotypic data with pigmentation traits was analysed via logistic regression. Web-based tools for predicting the effect of genetic variants in microRNA-binding sites in 3'UTR gene regions were also used. Seven 3'UTR SNPs showed a potential implication in melanoma risk phenotypes. This association is especially noticeable for two of them, rs2325813 in the MLPH gene and rs752107 in the WNT3A gene. These two SNPs were predicted to disrupt a miRNA-binding site and to impact on miRNA-mRNA interaction. To our knowledge, this is the first time that these two 3'UTR SNPs have been associated with sun-sensitivity traits. We state the potential implication of these SNPs in human pigmentation and sensitivity to sunlight, possibly as a result of changes in the level of gene expression through the disruption of putative miRNA-binding sites.
Subject(s)
3' Untranslated Regions/genetics , Adaptor Proteins, Signal Transducing/genetics , Melanoma/genetics , MicroRNAs/metabolism , RNA, Messenger/metabolism , Skin Neoplasms/genetics , Skin Pigmentation/genetics , Wnt3A Protein/genetics , Binding Sites , Case-Control Studies , Eye Color/genetics , Gene Frequency , Genetic Predisposition to Disease , Hair Color/genetics , Humans , Lentigo/genetics , MicroRNAs/genetics , Phenotype , Photosensitivity Disorders/genetics , Polymorphism, Single Nucleotide , Protective Factors , RNA, Messenger/genetics , Risk Factors , Spain , White People/geneticsABSTRACT
BACKGROUND: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes. MATERIALS AND METHODS: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings. RESULTS: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them. CONCLUSIONS: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.