Genome-wide analysis of constitutional DNA methylation in familial melanoma

Abstract

Background: Heritable epigenetic alterations have been proposed as an explanation for familial clustering of melanoma. Here we performed genome-wide DNA methylation analysis on affected family members not carrying pathogenic variants in established melanoma susceptibility genes, compared with healthy volunteers. Results: All melanoma susceptibility genes showed the absence of epimutations in familial melanoma patients, and no loss of imprinting was detected. Unbiased genome-wide DNA methylation analysis revealed significantly different levels of methylation in single CpG sites. The methylation level differences were small and did not affect reported tumour predisposition genes. Conclusion: Our results provide no support for heritable epimutations as a cause of familial melanoma.

New Insights into Melanoma Tumor Syndromes

“…Limitations of this study include J o u r n a l P r e -p r o o f the small number of families studied, and any causative epimutation may occur in a subset of melanoma families (and unlikely to be common in all). In addition, samples were interrogated on a 450K Illumina array that interrogated methylation status of CpG sites in all gene promoters but that did not cover other possible regulatory sequences (Salgado et al 2020). Future research focused on additional epigenetic mechanisms, including non-coding RNA, will continue to help elucidate unexplained predisposition to hereditary melanoma.…”

“…A more recent report analyzed five Dutch families, with at least three melanoma cases in different generations, for associated DNA methylation alterations. The authors concluded that despite several clustered epimutations discovered, these candidates were unlikely driving the predisposition ( Salgado et al., 2020 ). Limitations of this study include the small number of families studied, and any causative epimutation may occur in a subset of melanoma families (and unlikely to be common in all).…”