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Combinations of low-frequency genetic variants might predispose to familial pancreatic cancer.
J. Pers. Med. 11:631 (2021)
Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10-15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Familial Pancreatic Cancer ; Genetic Variants ; Wgs; Breast-cancer; Germline Mutations; Acad9 Mutations; Increased Risk; Identification; Prevalence; Brca2; Refinement; Expression; Survival
ISSN (print) / ISBN
2075-4426
e-ISSN
2075-4426
Zeitschrift
Journal of Personalized Medicine
Quellenangaben
Band: 11,
Heft: 7,
Artikelnummer: 631
Verlag
MDPI
Verlagsort
Basel, Switzerland
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Genetic Epidemiology (IGE)
Förderungen
Deutsche Krebshilfe