A novel CpG island methylation panel predicts survival in lung adenocarcinomas

Abstract

The lack of clinically useful biomarkers compromise the personalized management of lung adenocarcinomas (ADCs); epigenetic events and DNA methylation in particular have exhibited potential value as biomarkers. By comparing genome-wide DNA methylation data of paired lung ADCs and normal tissues from 6 public datasets, cancer-specific CpG island (CGI) methylation changes were identified with a pre-specified criterion. Correlations between DNA methylation and expression data for each gene were assessed by Pearson correlation analysis. A prognostically relevant CGI methylation signature was constructed by risk-score analysis, and was validated using a training-validation approach. Survival data were analyzed by log-rank test and Cox regression model. In total, 134 lung ADC-specific CGI CpGs were identified, among which, a panel of 9 CGI loci were selected as prognostic candidates, and were used to construct a risk-score signature. The novel CGI methylation signature was identified to classify distinct prognostic subgroups across different datasets, and was demonstrated to be a potent independent prognostic factor for overall survival time of patients with lung ADCs. In addition, it was identified that cancer-specific CGI hypomethylation of RPL39L , along with the corresponding gene expression, provided optimized prognostication of lung ADCs. In summary, cancer-specific CGI methylation aberrations are optimal candidates for novel biomarkers of lung ADCs; the 9-CpG methylation panel and hypomethylation of RPL39L exhibited particularly promising significance.

Identification and validation of novel DNA methylation markers for early diagnosis of lung adenocarcinoma

“…A number of researches have also been done to identify cancerspecific DNA methylation markers in lung cancer patients. Yan et al [54] identified a panel with nine CpGs using a combined public methylation datasets and constructed a prognosis model to predict survival in LUAD patients. Diaz-Lagares et al [13] identified four methylation markers including BCAT1, CDO1, TRIM58, and ZNF177 and achieved 85% AUC on a regression model trained from the combination of four markers in bronchoalveolar lavages from patients with lung cancer.…”

“…Yan et al . [54] identified a panel with nine CpGs using a combined public methylation datasets and constructed a prognosis model to predict survival in LUAD patients. Diaz‐Lagares et al .…”

Genome-wide promoter methylation profiling in a cellular model of melanoma progression reveals markers of malignancy and metastasis that predict melanoma survival

“…However, survival multivariate analyses were not evaluated for these probes. This multivariate approach has already been conducted for clear cell renal carcinoma [ 59 ], leukemia [ 60 ], esophageal squamous cell carcinoma [ 61 ], colorectal cancer [ 62 ], lung adenocarcinoma [ 63 ], among others. Future validation of the identified CpGs methylation panels in a new cohort will be deemed necessary for their use in the clinic.…”

Ribosomal protein RPL39L is an efficiency factor in the cotranslational folding of proteins with alpha helical domains

“…Among these, autosomal-chromosome-encoded paralogs of X chromosome-linked RPs have strong expression bias for the male germ cell lineage, where they have been linked to highly specialized functions: RPL10L takes over the function of RPL10 upon X chromosome inactivation in the meiotic phase of spermatogenesis 3 , and RPL39L was implicated in the translation of long-lived, sperm cell-specific proteins 4 . However, the RPL39L mRNA was also observed in other cell types, including ovarian 5 and breast cancers 2 , as well as in lung cancer 6 and neuroblastoma 4 cell lines. Gene amplifications 7 and the hypomethylation of a specific CpG island 6 were proposed as mechanisms underlying RPL39L expression in cancers.…”

“…However, the RPL39L mRNA was also observed in other cell types, including ovarian 5 and breast cancers 2 , as well as in lung cancer 6 and neuroblastoma 4 cell lines. Gene amplifications 7 and the hypomethylation of a specific CpG island 6 were proposed as mechanisms underlying RPL39L expression in cancers. These observations suggest that RPL39L has a general function, extending beyond the translation of long-lived sperm cell proteins.…”