Epigenetics, BRCA, and Inherited Cancers: Dr. Newman Connects the Dots

William Newman, PhD, FRCP, is professor of translational genomic medicine at the University of Manchester and director of the Greater Manchester Genomic Medicine Centre in Manchester, England. Cancer Network spoke with Professor Newman about his team’s research into the roles of epigenetic silencing in heritable cancer syndromes.

Cancer Network: What is epigenetic silencing and what are its roles in normal, healthy gene expression and cell biology?

Dr. Newman: DNA is made up of four building blocks (nucleotides): A (adenine), C (cytosine), G (guanine) and T (thymine). The sequence of these forms genes which provide the information to produce RNA, which allows the formation of proteins.

Near the start of genes in an area called the promoter, the sequence often contains a large number of Cs and Gs. These are often present in CG pairs. The C in this pair can be modified by the addition of a methyl chemical group. This does not change the DNA sequence and so is called an epigenetic change. When many Cs are modified in this way it results in a switching off of the DNA in its ability to make RNA. This is called epigenetic silencing.

There are many things that can result in epigenetic silencing, including diet. Different genes are switched on or off in different tissues in the body and at different times in development by this process. Occasionally a genetic change called a secondary epimutation can result in methylation of the promoter.

Cancer Network: What are the emerging roles of epigenetic silencing in tumorigenesis and tumor progression?

Dr. Newman: We know that there are two main classes of genes important in cancer development. Oncogenes are overactive genes or accelerators whereas tumor suppressor genes act as the brakes on growth. We know that BRCA1 and BRCA2 are tumor suppressor genes. Therefore, a mechanism like epigenetic silencing that results in turning off of the gene would be in keeping with the inactivation of a tumor suppressor gene like BRCA1.

We know that epigenetic silencing is a relatively common mechanism in cancer tissue affecting one or both copies of a gene. Many researchers have been looking at ways to reverse this process in cancer as a potential treatment.

Cancer Network: Your team recently reported findings about the role of epigenetic silencing in heritable or familial breast and ovarian cancer syndromes. How did you go about conducting that study and what did you find?

Dr. Newman: We identified a number of women where many family members had been affected by breast or ovarian cancer. Routine testing of the BRCA1 and BRCA2 genes did not identify any genetic change that would explain the diagnosis. We decided to look at the BRCA1 gene in more detail by a number of techniques to see if the promoter was methylated too much (hypermethylated). If so, this could mean that the BRCA1 gene was not working effectively. In two families we found that the promoter of the BRCA1 gene was hypermethylated in women affected by breast or ovarian cancer. We then found that a change outside of the BRCA1 gene resulted in this switching off of the BRCA1 gene.

Cancer Network: What’s next?

Dr. Newman: Other groups have already shown that epigenetic silencing is important as a cause of inherited forms of bowel cancer. It is very likely that other causes of inherited bowel, breast, or ovarian cancers that have not been found by routine genetic testing, could be due to epigenetic silencing.