Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes.
Cancer genomics
Cancer predisposition gene
Mendelian disease-associated gene
Pathogenic variant
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
25 Dec 2023
25 Dec 2023
Historique:
received:
12
07
2023
accepted:
30
10
2023
medline:
25
12
2023
pubmed:
25
12
2023
entrez:
24
12
2023
Statut:
epublish
Résumé
Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples. In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%). Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.
Sections du résumé
BACKGROUND
BACKGROUND
Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations.
METHODS
METHODS
Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples.
RESULTS
RESULTS
In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%).
CONCLUSIONS
CONCLUSIONS
Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.
Identifiants
pubmed: 38143269
doi: 10.1186/s13073-023-01252-w
pii: 10.1186/s13073-023-01252-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
107Subventions
Organisme : Agencia Estatal de Investigación
ID : PID2019-109571RA-I00
Organisme : Korea Health Industry Development Institute
ID : HI18C1876
Pays : Republic of Korea
Organisme : National Research Foundation of Korea
ID : 2021R1A2C3005360
Organisme : College of Medicine, Seoul National University
ID : 1120190020
Organisme : Seoul National University Hospital
ID : 03-2020-0380
Informations de copyright
© 2023. The Author(s).
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