Some cancers (e.g., breast or prostate) are readily diagnosed based on the organ in which they arise. Other cancer types (such as central nervous system [CNS] or sarcomas) are more difficult to diagnose. Tumors in these tissue types may have similar histologies but very different biologic and prognostic characteristics. Distinguishing these can be addressed using DNA methylation (DNAm) analysis. Another difficult scenario addressed by DNAm is cancer originating from an unknown primary: disease that is metastatic at diagnosis, but the primary cancer it arose from is unclear.

DNAm analysis is increasingly incorporated into the diagnostic investigation of various cancers due to its precision in defining specific tumor types, especially those that evade definition by other types of molecular and pathologic analyses (i.e., some brain tumors). For these situations, DNAm analysis is likely superior to gene expression signatures and is closer to application in clinical practice. DNAm signatures can also aid in risk assessment, diagnosis, and prognostication.

Cancer, although conventionally considered a genetic disorder, typically involves genome- wide epigenetic dysregulation, including alterations to DNAm, histone modifications, chromatin remodeling, and microRNA. These changes can support the development of cancer by a variety of mechanisms. There is generalized DNAm dysregulation in cancer, which contributes to tumor development in a variety of ways. Generally, CpG islands near gene promoters will gain methylation, which can be associated with changes in that gene’s expression. Conversely, hypomethylation events are more common but not associated with specific genomic features. It is unclear whether hypomethylation in cancer plays a functional role, but it appears to be related to genome instability, manifested through cytogenetic events such as aneuploidy. Furthermore, silencing of certain critical homeostatic genes (e.g., DNA repair genes) can lead to MMR deficiency and hypermutability.

Further genome- wide alterations in DNAm can also be downstream consequences of variants in chromatin modifier genes (e.g., genome- wide hypermethylation due to DNMT3A gain of function or TET2 loss of function). Finally, loss- of- function sequence variants in epigenetic regulators have been identified as a hall mark of etiology in several cancers: in certain hematologic malignancies and variants in epigenetic regulators, including MLL1 and CBP/ p300, which normally mediate lineage specification/ differentiation and cause blocks in transitions to correct commitment pathways, resulting in proliferation of undifferentiated cells that manifest as leukemia. In brain tumors, H3- K27M plays a role in midline glioma development. Epigenetic changes involving chromosome 11p15.5 predispose to Wilms tumor and hepatoblastoma, as in Beckwith- Wiedemann syndrome.

Improved Diagnostic Yield with Methylation Testing

 The introduction of genome- wide DNAm profiling of tumors has been transformative in diagnostics. Importantly, DNAm- based tumor classification is as reliable as gene expression; it has emerged as a promising approach to differentiate tumor types and to improve diagnostics and prognostics. This is exemplified by CNS tumors and sarcomas, which can be more precisely defined by DNAm profiling than with traditional pathologic subgroups. This results from DNAm not only providing data about the current state of cellular modification but defining the tumor’s cell type of origin. It appears that the state of cell differentiation at the time of tumor initiation remains relatively stable during tumor development/ progression. Furthermore, DNAm, as a method of tumor subgrouping, provides a means to classify medulloblastoma subgroups for clinical trials and therapy modification. The World Health Organization (WHO) now recognizes medulloblastoma as four different diseases based on these subgroups initially defined by DNAm.

Therapies Targeting Epigenetic Modifications

 Epigenetic changes are reversible and therefore represent a viable target for therapeutic intervention. In the cancer realm, DNAm signatures are not only used for treatment selection, based on optimized diagnostics, but also to identify new treatment targets. Significant progress has been made in the development of pharmaceutical agents that target histones and DNAm. Some, including DNA methyltransferase inhibitors, which reverse aberrant hypermethylation, have been approved for clinical use for treatment of a variety of cancers, including hematologic malignancies and solid tumors. There are several other epigenetic agents currently available as standard- of- care cancer treatments. Romidepsin, a histone deacetylase, has been approved by the US Food and Drug Administration for cutaneous T- cell lymphoma— a painful and disfiguring condition. Positive response rates are ~30%, and the median duration of response is longer than 1 year.

As these epigenetic drugs are not curative, they are frequently combined with other treatments, including classic chemotherapies and immune checkpoint inhibi tors, to broaden response rates among patients. In summary, although epigenetic therapies are still a work in progress, chromatin remains an important therapeutic target for investigation.

One of the biggest limitations of epitargeted drug therapies is that they target epigenetic marks nonspecifically; there need to be more tailored therapies to reduce harm and improve outcomes.

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مواضيع ذات صلة

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

Screening for Genetic Susceptibility to Disease

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Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes

Genetic Basis of Cancer

Conditional Mutations Can Be Used to Study Essential Genes in Yeast

Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity

Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function