Abstract
Immortality is an essential characteristic of cancer cells; a recent transcriptomic study of epithelial cell immortalization has linked epigenetic silencing of the long noncoding RNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) to this process. This study evaluated the epigenetic and transcriptional state of MORT in two premalignant conditions-ductal carcinomas in situ and colon adenomas. Results show that MORT silencing is an early epigenetic event in human carcinogenesis, likely occurring near the point where premalignant cells gain immortality; this epigenetic silencing is maintained throughout malignant transformation and metastatic growth. Additional associations between MORT loss and clinical and molecular features of breast tumors showed that silencing of MORT occurs predominantly in luminal, receptor-positive breast cancer; is associated with overexpression of CCND1 and mutations of GATA3; and is negatively correlated with TP53 mutations. Taken in toto, MORT silencing occurs early in breast carcinogenesis, probably during cellular immortalization, and precedes the development of invasive luminal breast cancer.