Interpreting Sequence Variation in PDAC-Predisposing Genes Using a Multi-Tier Annotation Approach Performed at the Gene, Patient, and Cohort Level.
genetic predisposition
genomic data interpretation
medical oncology
pancreatic cancer
precision oncology
structural bioinformatics
survival analysis
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2021
2021
Historique:
received:
15
09
2020
accepted:
21
01
2021
entrez:
22
3
2021
pubmed:
23
3
2021
medline:
23
3
2021
Statut:
epublish
Résumé
We investigated germline variation in pancreatic ductal adenocarcinoma (PDAC) predisposition genes in 535 patients, using a custom-built panel and a new complementary bioinformatic approach. Our panel assessed genes belonging to DNA repair, cell cycle checkpoints, migration, and preneoplastic pancreatic conditions. Our bioinformatics approach integrated annotations of variants by using data derived from both germline and somatic references. This integrated approach with expanded evidence enabled us to consider patterns even among private mutations, supporting a functional role for certain alleles, which we believe enhances individualized medicine beyond classic gene-centric approaches. Concurrent evaluation of three levels of evidence, at the gene, sample, and cohort level, has not been previously done. Overall, we identified in PDAC patient germline samples, 12% with mutations previously observed in pancreatic cancers, 23% with mutations previously discovered by sequencing other human tumors, and 46% with mutations with germline associations to cancer. Non-polymorphic protein-coding pathogenic variants were found in 18.4% of patient samples. Moreover, among patients with metastatic PDAC, 16% carried at least one pathogenic variant, and this subgroup was found to have an improved overall survival (22.0 months versus 9.8; p=0.008) despite a higher pre-treatment CA19-9 level (p=0.02). Genetic alterations in DNA damage repair genes were associated with longer overall survival among patients who underwent resection surgery (92 months
Identifiants
pubmed: 33747920
doi: 10.3389/fonc.2021.606820
pmc: PMC7973372
doi:
Types de publication
Journal Article
Langues
eng
Pagination
606820Subventions
Organisme : NCI NIH HHS
ID : R01 CA178627
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247898
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK052913
Pays : United States
Informations de copyright
Copyright © 2021 Zimmermann, Mathison, Stodola, Evans, Abrudan, Demos, Tschannen, Aldakkak, Geurts, Lomberk, Tsai and Urrutia.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
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