Osaka University researchers identified key biological pathways driving the development of neuroendocrine gastrointestinal carcinoma, a rare and deadly cancer.

Osaka University researchers studied a highly lethal form of cancer in a large group of patients and identified the genetic factors that contribute to fatal outcomes.

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, in a study published in Cancer Discovery.

NECs are malignancies that begin in any epithelial organ of the body, but most commonly in the digestive system, specifically the pancreas. Aside from the fact that NEC is uncommon cancer, people with NEC do not generally have surgery, making tissue samples suitable for research purposes difficult to come by.

“Because of this, the genetic changes that contribute to the development of this cancer have remained largely unexplored until now,” said 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.”

On tissue samples from patients, the researchers performed a number of techniques, including whole-genome sequencing, transcriptome sequencing, DNA methylation analysis, assay of transposase accessible chromatin sequencing, and whole-exome sequencing, to examine the genetic basis of NEC.

“The results provided us with an unprecedented level of insight into the pathogenic mechanisms of NEC,” Tatsuhiro Shibata, senior author added.

“For example, we found that pancreatic NECs are genetically distinct from pancreatic neuroendocrine tumors and may not be involved in the same carcinogenesis.”

Structural variations, which involve the insertion, deletion, or inversion of a chromosome, were considerably more common in nonpancreatic NECs than in pancreatic NECs. Furthermore, based on genetic traits, pancreatic NECs might be divided into two categories (“ductal-type” and “acinar-type”).

Intriguingly, the researchers discovered unusually high levels of methylation on the promoter of a transcription factor linked to NEC; a previously unknown genetic event in which two genes fused, creating a new hybrid gene that disrupted cellular function; and deletion of an RNA splicing factor not previously 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,” explained Yachida.

Considering how much research has been done on this cancer, it is likely that the findings will lead to better treatments for people who have it. In some of these patients, drugs already on the market could be used to target the genomic changes that led to their disease, and the targets identified in this study could even lead to the development of new drugs.

Source: 10.1158/2159-8290.CD-21-0669

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