NEW YORK (GenomeWeb) – Three main mutational signatures most often mark esophageal squamous cell carcinomas from China, according to a study published online today in the American Journal of Human Genetics.
Chinese researchers did whole-exome sequencing on matched tumor-normal samples from 90 individuals with esophageal squamous cell carcinoma from China's Taihang Mountains and whole-genome sequencing on samples from another 14 individuals.
When the team analyzed the sequences alongside 88 ESCCs that were previously sequenced for a study done by the International Cancer Genome Consortium, it narrowed in on three sets of recurrent nucleotide substitution patterns in the tumors, including a mutational signature suspected of stemming from glitches in genes coding for cytidine deaminase enzymes in the APOBEC family.
"A signature attributed to the APOBEC family of cytidine deaminases was predominant in ESCC individuals, reflecting that this gene family contributes to cytosine mutation clusters in ESCC and cancer susceptibility through APOBEC-dependent mutational processes," co-senior authors Qimin Zhan, with Shanxi Medical University, and Yongping Cui, with the Chinese Academy of Medical Sciences and Peking Union Medical College, and their colleagues wrote.
In contrast, the authors did not detect in the tumors the sort of DNA damage patterns that have been linked to smoking, despite a self-reported smoking history in the majority of patients tested, stirring their suspicion that there might be other, yet undocumented mutational signatures associated with smoking.
The team noted that esophageal cancer outcomes tend to remain quite grim, with just around one-tenth to one-quarter of patients surviving for at least five years. The majority of global ESCC cases — an estimated 70 percent — occur in China, and individuals from the Taihang Mountains in the country's central north have particularly high rates of the disease.
In contrast to Western countries, where factors such as tobacco or alcohol abuse are believed to be the main risk factors for ESCC, cases in the Taihang Mountains and other parts of China seem to be more closely tied to family history and/or dietary risk factors such as chewing betelnut.
To get a sense of how these and other risk factors impact the somatic mutations that arise in ESCC, the researchers captured protein-coding sequences from 90 matched tumor-normal samples using the NimbleGen SeqCap EZ exome array before sequencing the exomes to a median of 132-fold coverage with Illumina's HiSeq 2000.
They also used the Illumina instrument to do whole-genome sequencing on tumor and normal samples from another 14 individuals, covering each genome to a median depth of 65-fold.
The mutation rate for the tumors was on par with that described for ESCCs previously, the team reported, with just shy of four coding mutations in every million bases of whole-genome sequence and 2.4 non-silent mutations per million bases of exome sequence.
Cytosine to thymine swaps were common in the ESCCs, though the context of these substitutions depended on the mutational signature involved.
In the tumors containing the APOBEC-related mutational signature, for example, cytosine to guanine, cytosine to thymine, and cytosine to adenine substitutions occurred within a characteristic trinucleotide sequence context.
When they looked at frequently mutated ESCC genes, meanwhile, the researchers detected known cancer contributors, along with chromatin remodeling genes and genes that are suspected of acting as tumor suppressors in ESCC.
The latter group included the AJUBA, ZNF750, and FAT1 genes, which the team investigated in more detail in cell line experiments.
Finally, the researchers saw signs of excessive activity by PI3-kinase and hedgehog signaling pathways in more than half of the tumors, hinting that there may one day be a benefit to targeting such pathways therapeutically.