Early contribution of germline and nevi genetic alterations to a rapidly-progressing cutaneous melanoma patient: a case report.

BACKGROUND: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. CASE PRESENTATION: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. CONCLUSIONS: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.

Predicción de riesgo de cáncer de mama en mujeres sanas de población española basado en el estudio de variantes genéticas / Prediction of cancer risk based on study of genetic variants in healthy women in the Spanish population

Objetivo: Estratificación de la población general con base en las variantes genotípicas para seleccionar a aquellas mujeres de alto riesgo a desarrollar un cáncer de mama que puedan ser candidatas a un seguimiento individualizado. Material y métodos: Se ha realizado un estudio caso-control en 856 mujeres con cáncer de mama y 839 mujeres controles de la población general pareadas por edad, analizando la asociación entre el riesgo a desarrollar cáncer de mama y un grupo de variantes basado en 76 polimorfismos de un cambio de base (SNP) de susceptibilidad. Resultados: Se han establecido 2curvas de casos y controles con base en las odds ratio (OR) genotípicas que diferencian las 2poblaciones con significación estadística (p = 2,293×10-15). Asimismo, se ha estratificado la población de casos y controles e identificado un 14% de la población que se encontraría en el grupo de alto riesgo con una OR > 2 (> 25% probabilidades de desarrollar un cáncer de mama). Este grupo sería candidato a un seguimiento individualizado. Conclusiones: El Polygenic Risk Score es un predictor del riesgo del cáncer de mama independiente que puede ayudar a seleccionar mujeres con alto riesgo para establecer medidas de seguimiento y tratamiento individualizado en función del riesgo genético

Objective: To stratify the general population based on genotypic variants in order to select women at high risk of breast cancer who could be candidates for individualized follow-up. Material and methods: We performed a case-control study in 856 women with breast cancer and 839 aged-matched control women from the general population. We analysed the association between the risk of developing breast cancer and a group of variants based on 76 susceptibility single nucleotide polymorphisms. Results: Two case-control curves were established based on genotypic odds ratios (OR) that differentiated the 2populations with statistical significance (P=2.293×10-15). Stratification of the case-control population showed that 14% of the population would be at high risk, with an OR>2 (> 25% probability of developing breast cancer). Persons in this group would be candidates for individualized follow-up. Conclusions: The Polygenic Risk Score is an independent predictor of breast cancer risk that may help to select women at high risk, with a view to establishing individualised follow-up and treatment according to genetic risk

Microwave electromagnetic field regulates gene expression in T-lymphoblastoid leukemia CCRF-CEM cell line exposed to 900 MHz.

Electric, magnetic, and electromagnetic fields are ubiquitous in our society, and concerns have been expressed regarding possible adverse effects of these exposures. Research on Extremely Low-Frequency (ELF) magnetic fields has been performed for more than two decades, and the methodology and quality of studies have improved over time. Studies have consistently shown increased risk for childhood leukemia associated with ELF magnetic fields. There are still inadequate data for other outcomes. More recently, focus has shifted toward Radio Frequencies (RF) exposures from mobile telephony. There are no persuasive data suggesting a health risk, but this research field is still immature with regard to the quantity and quality of available data. This technology is constantly changing and there is a need for continued research on this issue. To investigate whether exposure to high-frequency electromagnetic fields (EMF) could induce adverse health effects, we cultured acute T-lymphoblastoid leukemia cells (CCRF-CEM) in the presence of 900 MHz MW-EMF generated by a transverse electromagnetic (TEM) cell at short and long exposure times. We evaluated the effect of high-frequency EMF on gene expression and we identified functional pathways influenced by 900 MHz MW-EMF exposure.