High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast

Abstract

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.

Keywords

FAK^6/7 / SRRM4 / neuroendocrine neoplasms / pancreas / breast

References

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Acknowledgements

This work was supported by the Key Project of the National Natural Science Foundation of China (No. 81830093), the National Key Research and Development Program of China (Nos. 2020YFC2002705, 2020YFA0803300, and 2022YFA1103900), the CAMS Innovation Fund for Medical Sciences (CIFMS; Nos. 2022-RC310-05 and 2021-RC310-003), the CAMS Initiative for Innovative Medicine (Nos. 2021-I2M-1-014, 2022-I2M-2-001, and 2021-I2M-1-021), and the National Natural Science Foundation of China (Nos. 82073092 and 82273076).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1009-7 and is accessible for authorized users. The supplementary material contains 3 supplementary tables and 3 supplementary figures.

Compliance with ethics guidelines

Conflicts of interest Dawei Xie, Zheng Wang, Beibei Sun, Liwei Qu, Musheng Zeng, Lin Feng, Mingzhou Guo, Jihui Hao, and Guizhen Wang declare that they have no conflict of interest. Guangbiao Zhou is the Executive Deputy Editor-in-Chief of Frontiers of Medicine, and he was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

The study was approved by the research ethics committee of the Cancer Hospital, Chinese Academy of Medical Sciences and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Additional informed consent was obtained from all patients, whose identifying information is included in this article.

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