Life science
Genomic Medicine, Drug discovery

Comprehensive genomic profiling of neuroendocrine
carcinomas of the gastrointestinal system
Department of Cancer Genome Informatics, Graduate School of Medicine
Professor Shinichi Yachidahttps://researchmap.jp/read0210591

Life science

Abstract
The neuroendocrine carcinoma of the gastrointestinal system(GIS-NEC) is a rare but highly malignant neoplasm. We analyzed
115 cases using whole-genome/exome sequencing, transcriptome
sequencing, DNA methylation assays, and ATAC-seq and found
GIS-NECs to be genetically distinct from neuroendocrine tumors(GIS-NETs) in the same location. Clear genomic differences werealso evident between pancreatic NECs (Panc-NECs) and non-pancreatic GIS-NECs (Nonpanc-NECs). Panc-NECs could be classified into two subgroups (i.e., ‘Ductal-type’ and ‘Acinar-type’) basedon genomic features. Alterations in TP53 and RB1 proved commonin GIS-NECs, and most Nonpanc-NECs with intact Rb demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterationsof the Notch gene family were characteristic of Nonpanc-NECs.
Transcription factors for neuroendocrine differentiation, especially
the SOX2 gene, appeared overexpressed in most GIS-NECs due
to hypermethylation of the promoter region. This comprehensive
study of genomic alterations in GIS-NECs uncovered several key
biological processes underlying the genesis of this very lethal formof cancer.

▍ Background & Results
NECs are cancers that originate in most epithelial organs of thebody and most often in the digestive system, typically the pancreas. In addition to NEC being rare cancer, patients with NEC do notoften undergo surgery, so tissue samples that can be used for research purposes are hard to find.
Structural variants, in which part of a chromosome is inserted,deleted, or inverted, were far more common in Nonpanc-NECs
than in Panc-NECs. In addition, Panc-NECs could be classified into
two groups (‘ductal-type’ and ‘acinar-type’) based on their genomic features. Intriguingly, the researchers also identified unusuallyhigh levels of methylation on the promoter of a transcription factor
associated with NEC; a previously unknown genetic event where
two genes became fused, creating a new hybrid gene (NET1AKR1C3/4) that disrupted cellular function; and deletion of an RNA
splicing factor (SNRNP70) that has not previously been linked toNEC.

▍ Significance of the research and Future perspective
Our study suggests that different types of NECs arise due tovery different sets of driver mutations and genomic changes, which
could have important implications for patients’ treatment. Given
that this is one of the most comprehensive studies of this cancer todate, it is likely that the findings will help develop new, more effective treatments for affected patients. Existing drugs could be usedin some of these patients to specifically target the genomic changes leading to disease. The targets defined in this study could evenpromote new drug discovery.

P a t e n t
Yachida, Shinichi; Totoki, Yasushi; Noë, Michaël et al. Comprehensive genomic profiling of neuroendocrine carcinomas of the gastrointestinal system.
Cancer Discovery. 2022, 12(3), p. 692-711, doi: 10.1158/2159-8290.CD-21-0669
UR
L https://www.med.osaka-u.ac.jp/activities/results/2021year/yachida2021-12-9
K e y w o r d refractory cancer, rare cancer, whole-genome sequencing
Tr e a t i s e