ARDC Research Link Australia

ORCID Profile
Orcid icon. 0000-0002-7680-158X

Current Organisation
Fundación para la investigación y la innovación biosanitaria del principado de asturias

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Publications

Publication

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Publisher: Springer Science and Business Media LLC

Date: 13-08-2018

DOI: 10.1038/S41467-018-05074-Y

Abstract: Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 in iduals and lung expression quantitative trait loci (eQTL) data on 409 in iduals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Publication

Protein-altering germline mutations implicate novel genes related to lung cancer development

Publisher: Springer Science and Business Media LLC

Date: 11-05-2020

DOI: 10.1038/S41467-020-15905-6

Abstract: Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 in iduals of European ancestry and investigated gene expression levels in 7,773 s les. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 −15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 −3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 −22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930 . Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Publication