Challenges and emerging strategies for genome-wide evaluation of loss of imprinting in cancer.

Genomic imprinting is the phenomenon in which only a single allele of a gene is expressed based on its parental origin, thereby deviating from the typical biallelic expression of autosomal genes. It is meticulously controlled by epigenetic mechanisms, particularly DNA methylation. Imprinted loci are crucial for regulating growth during early development, and anomalies in imprinting can lead to congenital syndromes such as Beckwith-Wiedemann's and Prader-Willi's. Similarly, many cancers exhibit dysregulated imprinting patterns, putatively contributing to tumour growth. Yet, the assessment of imprinting in cancer is complex due to technical challenges, impeding clinical research and the translation of novel insight to the clinic. This review starts with a general introduction to imprinting, its (dys)regulation and key clinical findings in cancer and beyond. Then, we summarize common methods used to characterize normal imprinting and aberrations in cancer. Subsequently, we discuss how the interpretation of such findings is complicated by technical challenges, such as tumour impurity, the requirement for heterozygosity to distinguish between maternal and paternal alleles and the presence of tissue- and transcript-specific imprinting patterns. We further delve into state-of-the-art methods able to mitigate these challenges. Finally, we discuss how future methodological innovations, particularly by integrating single-cell and single-molecule based methods, may further facilitate a straightforward characterization of imprinting dysregulation and its underlying causes, and guide the development of clinical tests. Thus, by integrating recent advances and proposing innovative approaches, our review aims to provide a comprehensive overview for cancer researchers and clinicians to facilitate cancer imprinting research and its translation to the clinic.