The study find taht the General Hospital (MGH) Cancer Center has found that, contrary to common assumptions, the fact that a specific genetic mutation frequently arises in particular tumors may not signify that the mutation drives cancer development and progression. Their article published in Science describes how DNA single strands that fold back on themselves in what is called a “hairpin” structure appear highly sensitive to mutation by a gene editing enzyme expressed in many cancers.
Mutation by a gene editing
But many of these mutation “hotspots” occur in genes that are totally unrelated to cancers; therefore including many in non coding areas of the genome. But “A typical cancer genome will have five to ten driver mutations and thousands or even millions of these ‘passenger’ mutations that are just along for the ride;” says Michael Lawrence, Ph.D., of the MGH Cancer Center; co-senior author of the Science article.
“The thinking has been that; if the exact same mutation occurs in many different patients’ cancers; it must confer a fitness advantage to the cancer cells. While the recurrence-based approach to identifying cancer driver genes has been successful; it’s also possible that certain positions in the genome are just very easy to mutate.”
Although much is know about how patterns of gene mutation are affect by small-scale structures such as the groups of three bases call trinucleotides or by the large-scale “compartments” into which DNA is organize in the nucleus; relatively little is know about the effects of “mesoscale” DNA structures that may extend 30 base pairs around the site of a mutation.
Previous investigation by others into breast cancer mutation hotspots associate with APOBEC enzymes identify DNA “palindromes” in which a specific sequence on one side of a mutation is repeat in reverse on the other side suggesting the stem-loop hairpin structure.
The MGH team’s analysis of data from The Cancer Genome Atlas and other sources focused on the potential influence of such mesoscale structures on the frequency and recurrence of mutations. They specifically investigated mutations associated with the APOBEC family of proteins; which among many other functions helps protect against viruses that enter cells by altering the viral genome.
Many types of cancer cells are known to activate APOBEC enzymes and; in contrast to other cancer-associated mutations that preferentially accumulate in a specific region of the genome; APOBEC-associated mutations are distributed evenly throughout the genome; frequently occurring in DNA hairpins.
Types of cancer cells
Their experiments revealed that the APOBEC3A enzyme commonly mutates cytosine bases located at the end of a hairpin loop; converting them into uracils; even in genes that have little or no association with cancer. In contrast; recurrent APOBEC-associated mutations in known driver genes were at ordinary sites in the genome; not the special hairpin sites that are especially easy for APOBEC3A to mutate.