NEW YORK (GenomeWeb) – New research suggests mutations in some cancer driver genes can arise in seemingly normal esophageal tissue as early as in childhood, becoming increasingly common with age and in response to alcohol or cigarettes.
"Driver-mutated clones emerge multifocally from early childhood and increase their number and size with aging, and ultimately replace almost the entire esophageal epithelium in the extremely elderly," corresponding and co-senior author Seishi Ogawa, a researcher in the Department of Pathology and Tumor Biology at Kyoto University, and his colleagues wrote, noting that the analysis pointed to "a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal esophageal epithelia."
Researchers from Japan, Canada, and Sweden performed exome or whole-genome sequencing on nearly 700 microscopic samples from 139 individuals with or without esophageal disease, including more than 90 individuals with esophageal squamous cell carcinoma (ESCC). Their results, appearing online today in Nature, pointed to age-, smoking-, and drinking-related expansions in clonal populations containing mutations in known driver genes such as NOTCH1 or PPM1D.
Even so, the team noted that the estimated lifetime risk of ESCC did not seem to rise significantly in elderly individuals, even with the expansion of driver gene mutations linked to aging. The results suggested that cancer risk was largely centered on individuals with additional risk factors such as smoking or drinking, though more research is needed to tease out the mutation differences in tissues that do become cancerous.
"Our knowledge is still limited regarding the mechanism of clonal evolution in normal tissues, and the way in which this differs from cancer evolution — these are important issues that remain to be addressed in understanding cancer and developing strategies for early detection, intervention, and even prevention of ESCC in high-risk patients," the authors concluded.
For the current analysis, the researchers sequenced the exomes of 25 physiologically normal esophageal epithelia samples and two cancer-affected tissues, identifying somatic mutations in all but one of the seemingly normal samples.
The team then sequenced the exomes of 157 physiologically normal punch biopsy samples from 21 individuals with ESCC or dysplasia and 40 healthy individuals, along with 20 tumor samples and a dozen samples marked by dysplasia. For 16 individuals, the group had access to samples from two to eight different regions of the esophagus.
Again, the researchers saw a slew of somatic mutations in physiologically normal epithelial samples, including all of the normal or tumor samples from individuals with ESCC. A subsequent analysis that included published data for hundreds more normal, dysplastic, and ESCC tumor samples suggested that ESCC, physiologically normal samples, and dysplastic samples are prone to four main mutational signatures.
When the team looked at new whole-genome sequence data for 13 single cell-derived colonies representing physiologically normal tissue from seven individuals, meanwhile, it tracked down driver gene mutations in seven of the colonies. These mutations seemed to rise with age, as did mutations in driver genes such as NOTCH1 and PPM1D that were profiled across physiologically normal epithelial samples from individuals between the ages of less than 20 years old and more than 80 years old.
Although such driver gene mutations typically turned up in physiologically unaltered tissue before late adolescence, the researchers noted, their results suggest clones containing these mutations expand significantly not only with age but also in individuals who reported heavy smoking and drinking — known lifestyle contributors to esophageal cancer risk.
"The remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which — depending on lifestyle risks — may affect cancer development," the authors wrote.