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Rigshospitalet - a part of Copenhagen University Hospital
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Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients

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  • Ming Tan
  • Klaus Brusgaard
  • Anne-Marie Gerdes
  • Michael Bau Mortensen
  • Sönke Detlefsen
  • Ove B Schaffalitzky de Muckadell
  • Maiken Thyregod Joergensen
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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.

Original languageEnglish
JournalClinical Genetics
Volume100
Issue number5
Pages (from-to)551-562
Number of pages12
ISSN0009-9163
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

    Research areas

  • cancer genes, familial pancreatic cancer, first-degree relatives, rare germline variants, whole genome sequencing

ID: 67849809