Whole genome sequencing identifies rare germline variants enriched in cancer related genes in firstdegree relatives of familial pancreatic cancer patients
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First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were over-represented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Clinical Genetics |
| Vol/bind | 100 |
| Udgave nummer | 5 |
| Sider (fra-til) | 551-562 |
| Antal sider | 12 |
| ISSN | 0009-9163 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
Rigshospitalet (RH)/Odense University Hospital (OUH) Research Fund, Grant/Award Number: A3183; Aase og Ejnar Danielsens Fond, Grant/Award Number: 18‐10‐0686; Dansk Kræftforsknings Fond (The Danish Cancer Research Fund); Fabrikant Einar Willumsens Mindelegat; Fonden til Lægevidenskabens Fremme (A.P. Møller Fonden); Kræftens Bekæmpelse (The Danish Cancer Society), Grant/Award Number: R218‐A13150; NEYE Fonden; Odense Pancreas Center (OPAC) Funding information
Funding Information:
This project was jointly supported by: The Danish Cancer Society (Kræftens Bekæmpelse) (ref.: R218‐A13150), NEYE Fonden, Odense Pancreas Center (OPAC), Fabrikant Einar Willumsens Mindelegat, The Danish Cancer Research Fund (Dansk Kræftforskningsfond), Fonden til Lægevidenskabens Fremme (A.P. Møller Fonden), the Rigshospitalet (RH)/Odense University Hospital (OUH) Research Fund (ref.: A3183), Aase og Ejnar Danielsens Fond (ref.: 18‐10‐0686).
Funding Information:
This project was jointly supported by: The Danish Cancer Society (Kr?ftens Bek?mpelse) (ref.: R218-A13150), NEYE Fonden, Odense Pancreas Center (OPAC), Fabrikant Einar Willumsens Mindelegat, The Danish Cancer Research Fund (Dansk Kr?ftforskningsfond), Fonden til L?gevidenskabens Fremme (A.P. M?ller Fonden), the Rigshospitalet (RH)/Odense University Hospital (OUH) Research Fund (ref.: A3183), Aase og Ejnar Danielsens Fond (ref.: 18-10-0686).
Publisher Copyright:
© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
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