Loss-of-Imprinting of HM13 Leads to Poor Prognosis in Clear Cell Renal Cell Carcinoma

Genomic imprinting refers to the epigenetic silencing of one of both alleles in a parent-of-origin-specific manner, particularly in genes regulating growth and development. Impaired genomic imprinting leading to the activation of the silenced allele, also called canonical loss-of-imprinting (LOI), is considered an early factor in oncogenesis. As LOI studies in clear cell renal cell carcinoma (ccRCC) are limited to IGF2, we performed a genome-wide analysis in 128 kidney normal solid tissue and 240 stage 1 ccRCC samples (TCGA RNA-seq data) to screen for canonical LOI in early oncogenesis. In ccRCC, we observed LOI (adj. p = 2.74 x 10(-3)) of HM13 (Histocompatibility Minor 13), a signal peptide peptidase involved in epitope generation. HM13 LOI samples featured HM13 overexpression, both compared to normal solid tissues (p = 3.00 x 10(-7)) and non-LOI (p = 1.27 x 10(-2)) samples. Upon adjustment for age and sex, HM13 expression was significantly associated with poor survival (p = 7.10 x 10(-5)). Moreover, HM13 overexpression consistently exacerbated with increasing tumor stage (p = 2.90 x 10(-8)). For IGF2, LOI was observed in normal solid tissues, but the prevalence did not increase in cancer. In conclusion, HM13 LOI is an early event in ccRCC, causing overexpression leading to poor prognosis.