Chief Science Correspondent
Epigenetic changes associated with the progresion of cervical cancer could be used in diagnostic screenings, according to a recent study conducted by University of California Irvine professor Mina Kalantari.
Traditionally, our DNA code stores information that directs the production of RNA, which is translated into different proteins that perform a variety of biological functions.
However, sometimes this process does not take place. In epigenetic silencing, certain DNA bases are inhibited through a process called methylation at certain regions, known as CpG islands. The mRNA is not transcribed, and the gene is not expressed.
Methylation can be induced by environmental factors, including stress, diet and chemical exposure. What makes epigenetics so critical is that, in some cases, this silencing is passed through generations.
Some studies have found that epigenetic modifications, including changes that cause cancer, could actually be passed from parent to offspring.
An estimated 4,000 women will die this year from cervical cancer, according to the American Cancer Society. Cervical cancer is primarily caused by infection by the human papillomavirus through sexual contact. Deaths from the disease have decreased significantly with widespread use of the Papanicolaou test (commonly known as the Pap smear), which can screen for potentially precancerous tissues. Additionally, certain tests can detect the presence of the virus itself in patients.
However, Kalantari notes that, because infection by HPV does not necessarily equate the development of cancer, a more sensitive test is necessary. The study found that the gene DAPK becomes increasingly more methylated during the progression of cervical cancer. Additionally, the team has identified four genes within HPV’s genome (HPV16, HPV18, HPV31 and HVP45) that become increasingly more methylated during the progression of cancer in the virus’ host.
The study included data from 552 high-risk patients from a local clinic, as well as 26 cervical carcinoma samples.
DAPK, which stands for death-associated protein kinase, is a protein associated with cell signaling and regulation of apoptosis (cell death). DAPK is associated with interferon activity, a process that induces “cell suicide” to prevent or curtail viral infection.
Thus, gradual epigenetic silencing of DAPK would make the cells progressively less effective in regulating HPV. Additionally, because of its role in regulating the cell cycle, the methylation of DAPK could promote excessive cell growth, resulting in the formation of tumors.
The mechanism by which DAPK becomes silenced via methylation is not yet fully understood. However, a 2012 study conducted at Johns Hopkins University linked DAPK methylation to the activity of small interfering RNAs. This process, commonly known as RNA interference, is thought to have arisen originally as an antiviral defense. The knockdown of DAPK has been linked to resistance of drugs for medical treatment.
The methylation of certain viral genes in the HPV genome is somewhat puzzling. Kalantari proposes that the methylation of these genes interrupts the normal life cycle of HPV, and consequently activates the expression of oncogenes, or cancer-causing molecules, within the patient’s genome.
Cervical cancer is often largely asymptomatic during early stages of progression, and thus, the disease can go undiagnosed in patients for a long time. Although the Pap smear test has been extremely effective in identifying potential cases, epigenetic screening could assist doctors in better understanding the progression of the disease.
Additionally, this information could be used for treatment of the disease in the future. Unlike genetic changes, epigenetic changes are not fixed, and could potentially be changed to manipulate gene expression.
Ultimately, cancer is a disease that is caused by an imbalance in the cell cycle. By regulating the elements that cause cell imbalances, cancer treatment could be less damaging and potentially more effective. This information could be particularly important if the epigenetic changes associated with cervical cancer are found to be heritable, which has not yet been determined.
For now, the Pap smear test remains the most reliable method for cervical cancer screening. The Centers for Disease Control recommends the test for all women 21-65 years of age undergo the test every three years. The test can be performed in a doctor’s office or clinic.
For more information on screening as well as risk factors associated with cervical cancer, visit http://www.cdc.gov/cancer/cervical/basic_info/screening.htm.