The Cancer Grand Challenges Mutographs study, a combined genetic and epidemiological analysis of data from eight countries with widely different incidences of esophageal squamous cell carcinomas (ESCC), has unexpectedly failed to identify mutational signatures indicating DNA damage that could account for global ESCC incidence variations.
"We found that the mutational signatures present in ESCC cases were extremely similar, regardless of where in the world the cancer occurred," said study co-lead author Sarah Moody, a postdoctoral research fellow at the Wellcome Sanger Institute in Cambridge, U.K.
"Our findings took us by surprise, given the differences in lifestyles and environments of the patients involved in the study," Moody told BioWorld Science.
However, the study did discover that two mutational signatures involved in activation of a family of evolutionarily conserved cytidine deaminases, termed apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC), were implicated in the development of ESCC.
Significantly, two APOBEC mutational signatures were found to be present in around 90% of ESCCs, which could suggest that a subset of tumors may be responsive to certain treatments, the authors reported in the October 18, 2021, issue of Nature Genetics.
"While we are not the first to find these two mutational signatures in this cancer type, we found them to be present at a much higher frequency than in previous studies, including in ESCC from both high and low incidence regions," said Moody.
Esophageal cancer is the sixth leading cause of cancer deaths worldwide, with the incidence of ESCC, the most common esophageal cancer subtype, showing particularly marked regional variations.
This is attributable partly to geographical and socioeconomic factors. For example, ESCC is especially common in areas of Iran, China and East Africa, but much less prevalent in high-income countries, including Japan and the U.K.
Epidemiological studies have also identified several potential environmental and lifestyle ESCC risk factors. Notably, tobacco smoking and alcohol consumption have been shown to increase the ESCC risk synergistically, predominantly in lower-risk regions.
However, environmental ESCC risk factors alone are not thought to fully explain observed regional incidence variations.
Genetic studies in human cancers and normal tissues have shown that both exogenous mutagenic exposures and endogenous processes generate distinctive mutational signatures.
While some of the known mutational signatures have well-established biological mechanisms, the etiology of others remains unknown.
If an unknown specific environmental mutagen were indeed driving the wide global ESCC incidence variations, this should be detectable by comparing mutational signatures of ESCC genomes from areas with different incidences.
While previous studies have provided an overview of the ESCC genome, some of which have included mutational signature analysis, many have been limited to whole-exome sequencing or have included only cases from high-incidence regions.
"Certain mutational signatures are enriched in the exome compared to the whole genome, so sequencing the whole genome gives us a more complete picture of the mutational signature landscape," Moody said.
"Only by sequencing cases from both high and low incidence regions would it have been possible to detect a mutational signature present or enriched only in high incidence areas and thus be able to explain the difference in incidence rates."
Moreover, to date there has been no comprehensive analysis of associations between mutational signatures and ESCC risk factors across multiple regions with varying incidences.
To address this, the Cancer Grand Challenges Mutographs study authors combined whole-genome sequencing and mutational signature analysis with comprehensive epidemiological questionnaire data, to study 552 ESCC genomes from 8 countries with different incidence rates.
Mutational profiles were found to be similar across all countries studied, while associations were identified between specific mutational signatures and ESCC risk factors for tobacco, alcohol and germline variants, with modest impacts on the mutation burden.
Moreover, there was no evidence of a mutational signature suggesting an exogenous exposure capable of explaining differences in ESCC incidence.
"We're certain that mutations do contribute to the development and incidence of ESCC, but our findings add to a growing body of evidence that some factors drive cancer without necessarily damaging DNA," said Sir Michael Stratton, leader of the Mutographs study team and director of the Wellcome Sanger Institute.
Importantly, APOBEC-associated mutational signatures single-base substitution (SBS) 2 and SBS13 were found in 88% and 91%, respectively, of the Mutograph study's ESCC cases.
On average, these two APOBEC SBS variants accounted for 25% of the mutation burden, indicating that APOBEC activation is a key step in ESCC tumor development.
"APOBEC is thought to protect against viral infections under normal circumstances, but it remains unclear why APOBEC targets the human genome in some cancers," said Moody.
"The almost universal presence of APOBEC associated mutational signatures suggests it is an important and perhaps mandatory step in ESCC development," she added.
"However, much more work remains to be done in investigating when and why APOBEC becomes activated in ESCC. This includes understanding more about the implications of this finding in terms of potential drug development, which was not explored in this study."
In addition, "the finding that there was no mutational signature capable of explaining the difference in ESCC incidence rates is important," Moody pointed out.
"This, together with other recent studies, provides an increasing body of evidence that not all carcinogens act by directly mutating DNA, but may act in some other way to increase the risk of developing cancer."
Importantly, "carcinogens which act in this manner may not be detectable using the approaches used in this study, which will inform future research not only into the mystery of ESCC incidence rates, but also potentially of other cancer types."