J Breast Cancer.  2017 Jun;20(2):198-202. 10.4048/jbc.2017.20.2.198.

Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes

• Vrba L
• Futscher B

• KMID: 2389758
• DOI: http://doi.org/10.4048/jbc.2017.20.2.198

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.

Keyword

Breast neoplasms; Carcinogenesis; DNA methylation; Gene silencing; Long noncoding RNA

MeSH Terms

Adenoma
Breast Neoplasms*
Breast*
Carcinogenesis
Colon
DNA Methylation
Epigenomics*
Epithelial Cells
Gene Silencing
Humans
Phenobarbital*
RNA
RNA, Long Noncoding
Phenobarbital
RNA
RNA, Long Noncoding

Figure

• 

  Figure 1 MORT gene silencing is early event in cancer. (A, B) DNA methylation of the MORT promoter in two independent cohorts of breast ductal carcinoma in situ (DCIS) patients. (C) DNA methylation of the MORT promoter in 44 pairs of primary breast tumors and lymph node metastasis. (D) DNA methylation of the MORT promoter as determined by reduced representation bisulfite sequencing in a DCIS cohort. (E, F) DNA methylation of the MORT promoter in two independent cohorts of colon adenomas and carcinomas. All data except (D) were obtained using the Illumina Human Methylation 450 platform. Where more than two groups are presented the p-value is for in situ lesions versus normal samples. IBC=invasive breast cancer.

• 

  Figure 2 DNA methylation mediated MORT gene silencing is linked to luminal, receptor positive breast cancers. (A) MORT expression level plotted versus MORT copy number. DNA methylation of the MORT promoter in receptor negative and receptor positive tumors estrogen receptor (ER) (B), progesterone receptor (PR) (C), and human epidermal growth factor receptor 2 (HER2) (D). (E) DNA methylation of the MORT promoter in triple negative (TN) tumors, tumors positive for at least one receptor and a group of normal samples (p-value is for contrast TN vs. receptor (+) tumors). (F) DNA methylation of the MORT promoter in breast tumors classified into subtypes according to PAM50 (p-values are for contrast of individual tumor subtypes vs. normal). (G) DNA methylation of the MORT promoter in samples from patients >60 years of age compared to those from patients ≤60. (H) Association between amplification of the cyclin D1 locus and DNA methylation of the MORT promoter. (I) DNA methylation of the MORT promoter in samples with wild type TP53 compared to samples with mutated TP53. (J) DNA methylation of the MORT promoter in samples with wild type GATA3 compared to samples with mutated GATA3. RPKM=reads per kilobase per million; CN=copy number; WT=wild type.

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