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Feb 1, 2010 (Vol. 30, No. 3)

Insights Accrue on Epigenetic Modification

Findings Could Transform Cancer Biology and Provide a Host of Benefits

  • The biomedical literature provides many examples when medical conditions that were classically viewed as a paradigm for genetic inheritance appear to be shaped by additional factors, which cannot be explained by DNA sequence variation alone. For example, there are several reports of monozygotic twins with Huntington disease who, despite harboring identical numbers of the CAG trinucleotide repeats, differ in their age at onset and in clinical presentation and progression.

    In addition to the genetic information required to establish an organism, recent decades have unveiled a previously unknown type of chromatin modification, known as epigenetic, which is defined as heritable DNA changes that are not encoded in the sequence itself. Unlike genetic modifications, the epigenetic ones are reversible, and increasingly appear to serve fundamental roles in cell differentiation and development.

    An important group of epigenetic modifiers is the polycomb group of proteins.  They were first described in Drosophila melanogaster, are conserved across species and function as critical regulators of several genes from embryogenesis to adulthood. Polycomb proteins reside in two multiprotein assemblies—polycomb repressive complexes PRC1 and PRC2, of which PRC2 is the only one currently known to di- and tri-methylate lysine 27 of histone H3—to establish repression of target genes. For this reason, the PRC2 complex has attracted considerable attention.

    “This complex is very exciting from the basic science point of view, it is important for cancer and, in addition, serves as the paradigm to understand the basic regulation of transcription,” says Kristian Helin, Ph.D., professor and director at the Biotech Research and Innovation Centre at the University of Copenhagen.

    One research effort in Dr. Helin’s lab focuses on understanding the biochemical organization and the biological function of this complex. Previously, Dr. Helin and collaborators showed that trimethylated histone H3 lysine 27 chromosomal marks that recruit PRC2 complexes are subsequently maintained on daughter strands during DNA replication. The team has proposed a model to explain how this epigenetic mark is maintained during interphase and inherited during cell proliferation, to preserve the gene-expression profile and the cellular identity during subsequent generations.

    “One key question is how these epigenetic modifications are targeted and recruited to specific locations, and how they regulate cellular events,” explains Dr. Helin. “In addition, an important question is whether this complex is going to be a good marker for certain types of cancer.”

    Epigenetics in general, not just DNA methylation, is going to be very powerful. The more we are learning about chromatin marks, the better we are able to understand the behavior of tumors and predict their aggressiveness,” explains Stephen B. Baylin, M.D., professor of cancer research and deputy director of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

    In most tissues, CpG islands around transcription start sites are largely unmethylated, but their methylation has been described in many tumors and can serve as potential biomarkers. One of the advantages of using epigenomic biomarkers is that, in most cases, DNA methylation changes precede clinical symptoms. “If there is a small abnormality that is not yet an invasive cancer, but a precancerous lesion, or a small tumor, many genes will have abnormal methylation, and that is probably true in many tissues,” says Dr. Baylin.

    Recent work conducted by Nita Ahuja, M.D.’s lab, located in Dr. Baylin’s group, in collaboration with investigators from Johns Hopkins Medical Institute, the National Institutes of Health, and Vrije University from Amsterdam, revealed that TFPI2 promoter methylation occurs as an early and frequent event during colorectal cancer, and promises to become a valuable epigenetic marker when used in combination with other noninvasive colorectal carcinoma screening tools.

    Another exciting application of epigenetic markers that emerged from a study led by Malcolm Brock, M.D., in the Baylin program, is in the molecular staging of malignant tumors. By examining abnormal methylation patterns in both the tumor and the lymph nodes of patients with non-small-cell lung cancer, a malignancy that frequently recurs subsequent to treatment, Dr. Brock and collaborators reported that promoter methylation of several genes, even in patients with stage I cancer with histologically negative lymph nodes, was associated with tumor recurrence.

    In addition, methylation of both p16 and CDH13 in the tumor and mediastinal lymph nodes was associated with a 15-fold higher relative risk of recurrence. “These tumors behaved, not like stage I, but like stage III tumors,” explains Dr. Baylin. “These results need to be validated in larger studies, and this is an example of using molecular biomarkers for the molecular restaging of the cancer, a very powerful approach. Biomarkers based on DNA methylation and other chromatin marks are going to be very useful, in the future, to grade tumors.”


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