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Nat Commun ; 11(1): 2220, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393777


Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. 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.

Adenocarcinoma/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias Pulmonares/genética , Idoso , Alelos , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA-Seq , Fatores de Risco
Int J Cancer ; 146(7): 2019-2026, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31872440


In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

Antineoplásicos/administração & dosagem , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Imunidade/efeitos dos fármacos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Oxaliplatina/administração & dosagem , Adulto , Idoso , Biomarcadores , Ablação por Cateter , Neoplasias Colorretais/metabolismo , Terapia Combinada , Feminino , Seguimentos , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/terapia , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Resultado do Tratamento
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756


The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373


Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
Nat Genet ; 49(7): 1126-1132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604730


Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fumar/epidemiologia , Homeostase do Telômero/genética