Hilda Polyánka

Neonatal Blue Light Phototherapy and Melanocytic Nevi: A Twin Study

BACKGROUND: Neonatal blue light phototherapy (NBLP) has been widely and successfully used for the treatment of neonatal jaundice to reduce the plasma concentration of bilirubin and, hence, to prevent kernicterus. Only a few and controversial data are available in the literature as to how NBLP influences melanocytic nevus development. OBJECTIVE: Our goal was to conduct a twin study with the aim of better understanding the role of NBLP in melanocytic nevus development. We also investigated the roles of other environmental and constitutional factors in nevus formation. METHODS: Fifty-nine monozygotic and dizygotic twins were included in this cross-sectional study. One of the twin members received NBLP, and the other did not. A whole-body skin examination was performed to determine the density of melanocytic skin lesions. The prevalence of benign pigmented uveal lesions was evaluated during a detailed ophthalmologic examination. A standardized questionnaire was used to assess data relating to constitutional, sun-exposure, and other variables. To search for possible gene-environmental interactions involved in the appearance of pigmented lesions, the melanocortin 1 receptor variants and the I439V polymorphism of histidine ammonia-lyase genes were also determined in the enrolled twins. RESULTS: NBLP was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions. No association was found between the examined gene polymorphisms and the number of pigmented alterations in the examined study group. CONCLUSIONS: Our data suggest that NBLP could well be a risk factor for melanocytic nevus development. Phototherapy with blue-light lamps is a standard and essential therapeutic modality in neonatal care; therefore, additional in vivo and in vitro studies are necessary to establish its potential long-term adverse effects.

The -308 G>A SNP of TNFA is a factor predisposing to chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarian individuals: Conclusions of a genetic study with multiple stratifications

Single nucleotide polymorphisms (SNPs) of the tumour necrosis factor alpha (TNFα) gene (TNFA) have been extensively studied and shown to be associated with an increased risk of the development of various chronic inflammatory diseases. Inflammation has been demonstrated to play a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFα is a key pro-inflammatory cytokine with important functions in these processes. In order to determine whether the well-known TNFA -308 G>A SNP has a role in a genetic predisposition to CRS in the Hungarian population, we analyzed our genomic collection containing control and CRS patient samples in a case-control study, and compared the genotype and allele frequencies. There was no significant difference in the observed genotype or allele frequencies between the controls and the total CRS group. However, after careful stratification of the patient group on the basis of the observed clinical symptoms, we found a significantly higher carriage rate of the rare A allele-containing genotypes among the CRS patients with nasal polyposis (NP) who also exhibited sensitivity to aspirin (acetylsalicylic acid, ASA(+)). It is concluded that genetic variants of the TNFA gene may affect the risk of CRS in a clinically well-defined group of CRSNP(+)ASA(+) patients in the Hungarian population. Our results also emphasize that the group of CRS patients is not homogenous in that patients exhibiting different clinical symptoms exist. Their carried genetic predisposing factors, and as a result, the exact molecular events leading to the development of various forms of CRS, may also differ.

The expressions of ABCC4 and ABCG2 xenobiotic transporters in human keratinocytes are proliferation-related

Xenobiotic transporters of the ATP-binding cassette (ABC) protein superfamily play important roles in maintaining the biochemical barrier of various tissues, but their precise functions in the skin are not yet known. Screening of the expressions of the known xenobiotic transporter genes in two in vitro keratinocyte differentiation models revealed that the ABCC4 and ABCG2 transporters are highly expressed in proliferating keratinocytes, their expressions decreasing along with differentiation. Abrogation of the ABCC4 and ABCG2 protein functions by siRNA-mediated silencing and chemical inhibition did not affect the proliferation of HaCaT cells. In contrast, disruption of the ABCG2 function had no effect on normal human epidermal keratinocyte proliferation, while the inhibition of ABCC-type transporters by probenecid resulted in a striking decrease in the proliferation of the cells. These results indicate that, besides their possible therapy-modulating effects, xenobiotic transporters may contribute significantly to other keratinocyte functions, such as cell proliferation.

UVB-dependent changes in the expression of fast-responding early genes is modulated by huCOP1 in keratinocytes

Ultraviolet (UV) B is the most prominent physical carcinogen in the environment leading to the development of various skin cancers. We have previously demonstrated that the human ortholog of the Arabidopsis thaliana constitutive photomorphogenesis 1 (COP1) protein, huCOP1, is expressed in keratinocytes in a UVB-regulated manner and is a negative regulator of p53 as a posttranslational modifier. However, it was not known whether huCOP1 plays a role in mediating the UVB-induced early transcriptional responses of human keratinocytes. In this study, we report that stable siRNA-mediated silencing of huCOP1 affects the UVB response of several genes within 2 h of irradiation, indicating that altered huCOP1 expression sensitizes the cells toward UVB. Pathway analysis identified a molecular network in which 13 of the 30 examined UVB-regulated genes were organized around three central proteins. Since the expression of the investigated genes was upregulated by UVB in the siCOP1 cell line, we hypothesize that huCOP1 is a repressor of the identified pathway. Several members of the network have been implicated previously in the pathogenesis of non-melanoma skin cancers; therefore, clarifying the role of huCOP1 in these skin diseases may have clinical relevance in the future.

Melanoma-Derived BRAFV600E Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion

Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAFV600E melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAFV600E protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAFV600E with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAFV600E mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAFV600E mutation or protein in the peritumoral stroma of BRAFWT melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome.

A conserved linkage group on chromosome 6, the 8.1 ancestral haplotype, is a predisposing factor of chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarians

Inflammation plays a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFα is a key pro-inflammatory cytokine in the pathogenesis of this disease. In our previous studies, we showed that the TNFA -308A allele is a genetic predisposition factor in a subgroup of aspirin-sensitive (ASA+) CRS patients suffering from nasal polyps (NP) in the Hungarian population. To determine whether the TNF -308A allele or the presence of a complex, extended ancestral haplotype (8.1AH) located on chromosome 6 is responsible for the previously observed genetic effect, we performed a case-control study for examining the frequency of 8.1AH carriers in controls and in subgroups of CRS patients. Our novel observations demonstrate that the presence of the 8.1AH may be responsible for the development of severe forms of CRS (CRSwNP, ASA+) and strengthen the clinical observation that CRS patients can be classified into clinically and genetically different subgroups.

Melanoma-Predisposing CDKN2A Mutations in Association with Breast Cancer: A Case-Study and Review of the Literature

The authors present the case of a 33-year-old female patient who developed melanoma, ductal adenocarcinoma of the breast and primary pancreas adenocarcinoma nearly simultaneously, but independently of each other. Past medical history of the patient was unremarkable, however, in her family history gastric, laryngeal and breast cancer was noted on the paternal side. The occurrence of multiple primary tumours in a relatively young individual, together with the family history of different malignancies, suggested that there might be genetic predisposition to the development of multiple tumours. In this chapter we present the case of the young female patient suffering from three independent primary tumours and review current data on the germ-line mutations detected to date in the CDKN2A gene, in view of the association not only with melanoma, but also with additional malignant diseases, such as pancreas carcinoma and breast cancer.