Epigenomics

Genetics and Epigenetics -- Nature's Pen-and-Pencil Set.

Gosden, RG & Feinberg, AP, 2007.  N. Eng. J. Med. 356(7): 731-733

Intro. paragraph

The sequence of the four nucleotides of the genetic code is like an indelible ink that, with rare exceptions, is faithfully transcribed from cell to cell and from generation to generation. But on top of this code lies another one, literally "epigenetic," which is represented by methyl groups added to the DNA base cytosine, as well as covalent changes in histone proteins around which the DNA is coiled. This epigenetic information is more like a code written in pencil in the margins around the DNA. Although the genome largely distinguishes one person from another, the epigenome, or epigenetic information, distinguishes one cell type from another, changing rapidly in early embryogenesis as cells differentiate. Mistakes that may arise during this process are thought to be erased in the same germ line. In this issue of the Journal, Hitchins et al. show that this eraser may leave smudges, potentially allowing disease to be transmitted epigenetically as well as genetically. . .

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Comments

This editorial gives a very brief yet clear illustration of epigenetic effects and how epigenomic changes can influence the onset, development and treatment of diseases by their affects on gene expression patterns.  As such, it is a good, basic introduction to the earlier paper by Hegi et al. and the current paper by Hitchins et al. (both listed below).

MGMT gene silencing and benefit from temozolomide in glioblastoma.

Hegi, M.E. et al., 2005. N. Engl. J. Med. 352(10):997-1003

Abstract

Background Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. Methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. Results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit

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Inheritance of a cancer-associated MLH1 germ-line epimutation.

Hitchins et al., 2007. N. Engl. J. Med. 356(7): 697-702

Abstract

Persons who have hypermethylation of one allele of MLH1 in somatic cells throughout the body (a germ-line epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the families of two such persons, we found evidence that the epimutation was transmitted from a mother to her son but was erased in his spermatozoa. The affected maternal allele was inherited by three other siblings from these two families, but in those offspring the allele had reverted to the normal active state. These findings demonstrate a novel pattern of inheritance of cancer susceptibility and are consistent with transgenerational epigenetic inheritance.

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Comments

The Epigenomics of Cancer.

Jones, PA & Baylin, SB, 2007. Cell 128(4):683-692.

Aberrant gene function and altered patterns of gene expression are key features of cancer. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause this dysregulation. Here, we review recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, and discuss the growing implications of these advances for strategies to control cancer.

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Comment:

A good introduction to basic concepts of epigenomics plus a clear illustration of its roles in cancer development and the possible resistance to chemotherapy.  This paper is very well illustrated for self-study and for use as a source of lecture material.

Predicting lung cancer by detecting aberrant promoter methylation in sputum.

Palmisano, WA et al., 2000.  Cancer Res. 60(21):5954-5958.

Abstract

Despite the promise of using DNA markers for the early detection of cancer, none has proven universally applicable to the most common and lethal forms of human malignancy. Lung carcinoma, the leading cause of tumor-related death, is a key example of a cancer for which mortality could be greatly reduced through the development of sensitive molecular markers detectable at the earliest stages of disease. By increasing the sensitivity of a PCR approach to detect methylated DNA sequences, we now demonstrate that aberrant methylation of the p16 and/or O6-methylguanine-DNA methyltransferase promoters can be detected in DNA from sputum in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. Moreover, the prevalence of these markers in sputum from cancer-free, high-risk subjects approximates lifetime risk for lung cancer. The use of aberrant gene methylation as a molecular marker system seems to offer a potentially powerful approach to population-based screening for the detection of lung cancer, and possibly the other common forms of human cancer.

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