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Researchers from Osaka University investigated a highly lethal form of cancer in a large group of patients, and identified the genetic culprits that lead to deadly outcomes.

In a study published in Cancer Discovery, a journal of the American Association for Cancer Research, researchers from Osaka University have thoroughly revealed the genetic basis of the pathogenesis of neuroendocrine carcinoma (NEC) of the gastrointestinal system, a rare and deadly cancer that is highly resistant to treatment.

NECs are cancers that originate in most epithelial organs of the body and most often in the digestive system, typically the pancreas. In addition to NEC being a rare cancer, patients with NEC do not often undergo surgery, so tissue samples that can be used for research purposes are hard to find.

“Because of this, the genetic changes that contribute to the development of this cancer have remained largely unexplored until now,” says lead author of the study Shinichi Yachida. “By taking part in an international collaboration, we were able to conduct a comprehensive genomic analysis of a relatively large number of cases.”

To investigate the genetic basis of NEC in these patients, the researchers performed a variety of analyses, including whole-genome sequencing, transcriptome sequencing, DNA methylation analysis, assay of transposase accessible chromatin sequencing, and whole-exome sequencing on tissue samples taken from patients.

“The results provided us with an unprecedented level of insight into the pathogenic mechanisms of NEC,” states Tatsuhiro Shibata, senior author. “For example, we found that pancreatic NECs are genetically distinct from pancreatic neuroendocrine tumors and may not be involved in the same carcinogenesis.”

Structural variants, in which part of a chromosome is inserted, deleted, or inverted, were far more common in nonpancreatic NECs than they were in pancreatic NECs. In addition, pancreatic NECs could be classified into two different groups (“ductal-type” and “acinar-type”) based on their genomic features. Intriguingly, the researchers also identified unusually high levels of methylation on the promoter of a transcription factor associated with NEC; a previously unknown genetic event where two genes became fused together, creating a new hybrid gene that disrupted cellular function; and deletion of an RNA splicing factor that has not previously been linked to NEC.

“Our study suggests that different types of NECs arise due to very different sets of driver mutations and genomic changes, which could have important implications for patients’ treatment,” explains Yachida.

Given that this is one of the most comprehensive studies of this cancer to date, it is likely that the findings will help develop new, more effective treatments for affected patients. Existing drugs could be used in some of these patients to specifically target the genomic changes leading to disease, and the targets defined in this study could even promote new drug discovery.