Whole genome sequencing identifies rare germline variants enriched in cancer related genes in firstdegree relatives of familial pancreatic cancer patients
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Whole genome sequencing identifies rare germline variants enriched in cancer related genes in firstdegree relatives of familial pancreatic cancer patients. / Tan, Ming; Brusgaard, Klaus; Gerdes, Anne Marie; Mortensen, Michael Bau; Detlefsen, Sönke; Schaffalitzky de Muckadell, Ove B.; Joergensen, Maiken Thyregod.
I: Clinical Genetics, Bind 100, Nr. 5, 2021, s. 551-562.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Whole genome sequencing identifies rare germline variants enriched in cancer related genes in firstdegree relatives of familial pancreatic cancer patients
AU - Tan, Ming
AU - Brusgaard, Klaus
AU - Gerdes, Anne Marie
AU - Mortensen, Michael Bau
AU - Detlefsen, Sönke
AU - Schaffalitzky de Muckadell, Ove B.
AU - Joergensen, Maiken Thyregod
N1 - Publisher Copyright: © 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - cancer genes
KW - familial pancreatic cancer
KW - first-degree relatives
KW - rare germline variants
KW - whole genome sequencing
U2 - 10.1111/cge.14038
DO - 10.1111/cge.14038
M3 - Journal article
C2 - 34313325
AN - SCOPUS:85111719859
VL - 100
SP - 551
EP - 562
JO - Clinical Genetics
JF - Clinical Genetics
SN - 0009-9163
IS - 5
ER -
ID: 304068253