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Title:
Genetics and epigenetic aging of patients diagnosed with cutaneous malignant melanoma
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Subject:
malignant melanoma ; risk factors ; age acceleration ; epigenetics ; SNP
Abstract:
Introduction. Skin cancers are the most common cancers, and of these, the most aggressive type is malignant melanoma. Due to its rapid growth rate, dynamic development and frequent metastases, it is the most difficult to treat and therefore has the worst prognosis and the highest mortality rate. According to the latest epidemiological data, the incidence of melanoma is rapidly increasing at an alarming rate compared to any other type of cancer. The reasons for the extreme increase are only partially understood. Skin melanoma is a cancer with a high cure rate when the disease is limited to the skin. Detection of melanoma at an early stage, better understanding of the risk factors that increase its occurrence and their prevention are a priority to reduce mortality. Currently, the concept of melanoma oncogenesis is considered to be a multifactorial process involving genetic, epigenetic and environmental factors. Identification of genetic, epigenetic and environmental factors affecting the formation of melanoma may lead to improved prevention and diagnosis of melanoma, as well as early diagnosis of patients with an increased risk of progression and better oncological results. Aim of the study. The aim of this doctoral dissertation was a comprehensive analysis of the pathogenesis of malignant melanoma of the skin, including the identification of environmen ; tal, epigenetic and genetic factors affecting the development of melanoma. In addition, for the first time in history, epigenetic age was characterized using different biological clocks based on DNA methylation, as well as age acceleration of patients diagnosed with malignant melanoma compared to the healthy population was determined. Material and methods. The study was conducted in a group of 202 patients (research group - 101 people, control group - 101 people). Patients with newly or previously diagnosed malignant melanoma of the skin were included in the research group. All study participants were interviewed using an extensive interview questionnaire. Venous blood was collected from all participants and a buccal mucosa swab was performed twice. Genome DNA methylation and SNP (Single Nucleotide Polymorphism) analyses of all study subjects were performed using Illumina's microarray technology (Infinium® Global Screening Array and Infinium® MethylationEPIC 850K, Illumina). Based on the collected detailed questionnaire data, an analysis of correlations between environmental factors, methylation data, SNP data and the occurrence of malignant melanoma was carried out, as well as the epigenetic age of patients was determined using various types of biological clocks based on DNA methylation. Results. The risk of developing malignant melanoma was sig ; nificantly increased by the lack of higher education, the use of a solarium, and at least one episode of sunburn in a lifetime. Patients diagnosed with malignant melanoma were characterized by more intense photoaging of the facial skin compared to the control group, however, skin aging did not correlate with epigenetic age. Patients diagnosed invasive malignant melanoma were characterized by lower pace of aging described by PoAm parameter than patients without diagnosed malignant melanoma of the skin. Moreover, patients with melanoma located on the face were characterized by a significantly higher average value of the DNAmTL parameter (i.e. telomere length estimated on the basis of DNA methylation) compared to patients with melanoma diagnosed in other less sun-exposed locations. A similar relationship was demonstrated between lentigo melanoma and superficial spreading melanoma. In this study, no direct correlation was found between methylation data, environmental factors and the occurrence of malignant melanoma of the skin. No new, previously unknown SNP variants increasing the susceptibility to malignant melanoma were identified. On the other hand, the studied population of Polish patients with malignant melanoma was characterized by a significant genetic predisposition to its development in terms of all previously discovered SNP markers characteri ; stic of melanoma in the European population. Conclusions. Cutaneous malignant melanoma is not accompanied by accelerated aging of the body. The slower pace of biological aging observed in patients with cutaneous malignant melanoma may suggest that they have a lower risk of developing age-related diseases, such as cardiovascular diseases or colorectal cancer, but this requires further studies. On the other hand, skin aging does not correlate with epigenetic age, so external appearance is not a good predictor of agerelated diseases. The pioneering results observed in this study seem to have very practical and interdisciplinary clinical implications.
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Degree grantor:
Rada Dyscypliny Nauki medyczne