Lung Cancer Predisposition Research Articles

Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.

Prédispositions génétiques au cancer bronchopulmonaire: Genetic predisposition to lung cancer

While thoracic oncologists are familiar with somatic pathogenic variants in lung cancer, they only have limited knowledge of genetic predisposition to the disease. Genetic predisposition refers to the presence of a germline pathogenic variant (present in the patient’s DNA) that is the main cause of the lung cancer diagnosis. This review article presents the major lung cancer predisposition syndromes, such as EFGR-associated syndrome and Li-Fraumeni. Identifying a genetic predisposition has consequences for the patient, for whom long-term lung cancer screening is warranted. Additionally, if the risk of other cancers is increased, as in Li-Fraumeni syndrome, the patient is offered multiorgan screening, including annual whole-body MRI. There are also implications for the family, as it then becomes necessary to identify other carriers among relatives, and offer them personalized surveillance.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Machine learning-based ensemble approach in prediction of lung cancer predisposition using XRCC1 gene polymorphism

The employment of machine learning approaches has shown promising results in predicting cancer. In the current study, polymorphisms data of five single nucleotide polymorphisms (SNPs) of DNA repair gene XRCC1 (XRCC1 399, XRCC1 194, XRCC1 206, XRCC1 632, XRCC1 280) of the north Indian population along with four smoking status data is considered as an input to the proposed ensemble model to predict the risk of individual susceptibility to the lung cancer. The prediction accuracy of the proposed ensemble model for cancer predisposition was found to be 85%. The model performance is also evaluated using sensitivity, specificity, precision and the Gini index, which is found in the range of 0.83–0.87. The proposed model also outperformed in all evaluation parameters when compared with the individual Model (LM, SVM, RF, KNN and baseline neural net). Collectively, current results suggest the potential of the proposed ensemble model in predicting the risk of cancer based on XRCC1 SNPs data. Communicated by Ramaswamy H. Sarma

POT1 germline pathogenic variants and evolving understanding of tumor spectrum: Evidence for lung cancer predisposition.

10511 Background: As a critical component of the shelterin complex, the protection of telomeres 1 protein (POT1) plays important roles in telomere length regulation and tumorigenesis. POT1 germline pathogenic/likely pathogenic variants (PVs) have been primarily linked to the development of melanoma, chronic lymphocytic leukemia, and glioma. Recent studies report POT1 PVs also predispose to other tumors such as certain sarcomas and thyroid cancer. Methods: To better understand the role of POT1 in the development of solid tumors, we explored the spectrum of POT1 germline variants in 6644 patients with POT1 sequencing performed utilizing the MSK-IMPACT assay. Results: In total, 91 POT1 germline rare variants (population frequency < 0.01%) were identified in our cohort in 90 patients across 47 cancer types. We found 16 POT1 PVs including frameshift variants (p.Ile49fs, p.Gln358fs, p.Asp617fs), a nonsense variant (p.Arg363Ter), a missense variant (p.Asp224Asn), and splice site variants (c.10-2A > C, c.1369+1G > T). One cutaneous melanoma patient, one uveal melanoma patient, and one glioma patient were identified to have POT1 PVs. Interestingly, 8 patients with germline POT1 PVs were diagnosed with lung cancer (7 with lung adenocarcinoma and one with small cell lung cancer). Three of these 7 patients with lung adenocarcinoma had biallelic inactivation of POT1 in their tumor. The proportions of POT1 PVs in MSK lung adenocarcinoma compared to the gnomAD non-cancer control cohort were statistically significantly different (odds ratio = 16.28, 95%CI = 6.52-33.54, P = 2.87e-06). Moreover, of the 90 patients with rare germline POT1 variants, 22 had POT1 biallelic inactivation, and 9 of these 22 were diagnosed with lung adenocarcinoma. Conclusions: Taken together, our study refines the role of POT1 germline variants in solid tumors and highlights an apparent association of POT1 PVs with lung adenocarcinoma development.

A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.

Rationale: Genome-wide association studies have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored. Objectives: To evaluate the role of human exomes in genetic predisposition to lung cancer. Methods: We performed exome-wide association studies to detect the association of exomes with lung cancer in 30,312 patients and 652,902 control subjects. A scalable and accurate implementation of a generalized mixed model was used to detect the association signals for loss-of-function, missense, and synonymous variants and gene-level sets. Furthermore, we performed association and Bayesian colocalization analyses to evaluate their relationships with intermediate exposures. Measurements and Main Results: We systematically analyzed 216,739 single-nucleotide variants in the human exome. The loss-of-function variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta (P values of meta-analysis) = 3.60 × 10-8] and rs202187871POT1 [Pmeta = 2.21 × 10-8]) and two synonymous variants (rs7447927TMEM173 [Pmeta = 1.32 × 10-9] and rs140624366ATRN [Pmeta = 2.97 × 10-9]). rs202197044TET3 was significantly associated with emphysema (odds ratio, 3.55; Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (β = 1.08; Pfdr (FDR corrected P value) = 3.76 × 10-53). Functional evidence of expression of quantitative trait loci, splicing quantitative trait loci, and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1 (protection of telomeres 1), RTEL1, BSG, and ZNF232. Conclusions: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.

Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.

Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

Abstract 5041: Multiple outcome linkage disequilibrium score regression for confounding independent genetic correlations

Abstract Introduction: Linkage disequilibrium score regression (LDSR) estimates the genetic correlation between traits. Currently genetic correlation is calculated in LDSR by regressing the product of genome wide association study SNP z-scores (Ztrait1 * Ztrait2) against the SNPs calculated linkage disequilibrium scores for a population. The slope of this regression accurately estimates the genetic covariance between the two traits. Genetic covariance is then normalized to a genetic correlation. No method exists for calculating multi-trait genetic correlations. Understanding the genetic correlation between two traits, conditional on the effects of a third trait, would help clarify the correlation in traits, after removing effects from confounding variables. Methods: To estimate genetic correlation between two traits independent of the effects of a third trait, we are developing a multiple outcome linkage disequilibrium score regression. To do this we set up a multivariate outcome regression on the linkage disequilbrium score, jointly modeling the products of z-scores for i) the trait of interest with the outcome of interest and ii) the trait of interest with the confouder. This process is similar to the steps of the usual implementation of LDSR, however in multiple outcome LDSR modeling the model coefficients, or the genetic covariances of the trait and the confounder will covary. This affords the opportunity for testing to jointly determine if the genetic covariances identified are jointly or independently significant. We have implemented this multiple outcome LDSR method and compared the results to standard outcome LDSR using data from the United Kingdom Biobank (UKBB) and the TRICL-OncoArray lung cancer (LC) consortium. We evaluated the UKBB trait of BMI and current smoking status, for their joint genetic correlation on overall LC outcomes. Results: Implementing LDSR, significant pairwise genetic correlation (rg) was observed between the UKBB trait of current smoking status, and the overall LC outcome (rg = 0.62 +/- 0.06, p = 7.17x10-25). Similarly, significant positive genetic correlation was observed between the UKBB trait of BMI and overall LC predisposition (rg = 0.20 +/- 0.03, p = 2.607x10-9). Using multiple outcome LDSR and jointly modeling BMI-LC susceptibility with smoking-LC susceptibility resulted in a BMI-LC genetic correlation of 0.0103, which was highly attenuated, and consistent with prior studies that show the BMI-LC association is modulated through smoking behavior. Conclusions: Multiple outcome linkage disequilibrium score regression allows for multiple-trait genetic covariances to be measured simultaneously and for effect estimates to be partially mitigated for the influence of a confounder. Further validation and sensitivity analysis is warranted to determine appropriate implementations and interpretations of this novel method. Citation Format: Rowland W. Pettit, Christopher I. Amos. Multiple outcome linkage disequilibrium score regression for confounding independent genetic correlations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5041.

The shared genetic architecture between epidemiological and behavioral traits with lung cancer

The complex polygenic nature of lung cancer is not fully characterized. Our study seeks to identify novel phenotypes associated with lung cancer using cross-trait linkage disequilibrium score regression (LDSR). We measured pairwise genetic correlation (rg) and SNP heritability (h2) between 347 traits and lung cancer risk using genome-wide association study summary statistics from the UKBB and OncoArray consortium. Further, we conducted analysis after removing genomic regions previously associated with smoking behaviors to mitigate potential confounding effects. We found significant negative genetic correlations between lung cancer risk and dietary behaviors, fitness metrics, educational attainment, and other psychosocial traits. Alcohol taken with meals (rg = − 0.41, h2 = 0.10, p = 1.33 × 10–16), increased fluid intelligence scores (rg = − 0.25, h2 = 0.22, p = 4.54 × 10–8), and the age at which full time education was completed (rg = − 0.45, h2 = 0.11, p = 1.24 × 10–20) demonstrated negative genetic correlation with lung cancer susceptibility. The body mass index was positively correlated with lung cancer risk (rg = 0.20, h2 = 0.25, p = 2.61 × 10–9). This analysis reveals shared genetic architecture between several traits and lung cancer predisposition. Future work should test for causal relationships and investigate common underlying genetic mechanisms across these genetically correlated traits.

21P Urethane-induced lung carcinogenesis in genetically edited C57Bl/6 mice with CHEK2 and GPRC5A heterozygous inactivating mutations

Some lung cancer (LC) patients carry germline truncating mutations in DNA repair or other cancer-related genes, however it is unclear whether these allelic variants play a causative role in LC predisposition, or, alternatively, are occasionally present in these subjects due to a chance. Case-control comparison is often not efficient due to rarity of gene-inactivating variants in population, therefore alternative approaches are required. We evaluated whether germ-line inactivation of GPRC5A and CHEK2 genes facilitates LC in mice. C57BL/6 mice with heterozygous inactivating mutations in the GPRC5A or CHEK2 genes were created using the CRISPR/Cas9 system. Donor eggs were obtained from the first generation of crossing mice of C57BL/6 (males) and CBA (females) inbred strains. Offspring mice F1 bearing inactivating mutations in GPRC5A and CHEK2 were used in further breeding with C57BL/6 wild-type strain for the study purposes. Altogether, 33 females and 21 males without mutations, 11 females and 19 males with mutations in CHEK2, and 13 females and 14 males with mutations in GPRC5A were analyzed. At the age of 3 months, mice were intraperitoneally injected with urethane (1 g/kg). The experiment was stopped after 45 weeks, all animals were autopsied and the lung tumor nodes were counted. In the wild-type (control) mice, the number of affected animals was 16/33 (48%) in females and 12/21 (57%) in males (pooled males/females: 28/54 (52%)). The rate of tumor development was not increased in CHEK2-heterozygous mice (females: 6/11 (55%); males: 7/19 (37%); pooled males/females: 13/30 (43%)). However, animals carrying GPRC5A heterozygous inactivating mutations showed a trend towards elevated occurrence of carcinogen-induced lung neoplasms (females: 9/13 (69%); males: 11/14 (79%); pooled males/females: 20/27 (74%); р = 0.06 when compared to controls). These data support evidences for the involvement of GPRC5A gene in pathogenesis of lung cancer.

Interaction between common variants of MDM2 and PPP1R13L and CD3EAP and TP53 SNPs in relation to lung cancer risk among Chinese.

BackgroundLung cancer is a complex disease that diagnosed the most common cancer and led cause of cancer death. MDM2 (MDM2 proto-oncogene) encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as TP53, for proteasomal degradation. Epidemiology studies have investigated the association of MDM2 single nucleotide polymorphisms (SNP) and interaction between genetic and environmental factors with lung cancer.MethodsThis Chinese case-control study comprised 627 cases and 633 controls explored the role of MDM2 five htSNPs (rs1690924, rs1846402, rs2291857, rs3730581 and rs3730635, haplotype-tagging SNP) tagging 95% of the common haplotypes across the gene and the interactions of MDM2, PPP1R13L, CD3EAP and TP53 in the same pathological pathway on lung cancer risk, together with smoking-duration.ResultsNone of the htSNPs in MDM2 were associated with lung cancer risk in co-dominant, dominant, recessive, and log-additive models (adjusted for smoking-duration). Haplotype analysis showed that global haplotype association was statistically significant (P=0.0036, adjusted for smoking-duration) and haplotype5 (rs1690924A-rs1846402G-rs2291857C-rs3730581G-rs3730635A) was associated with reduced risk of lung cancer [OR (95%) =0.52 (0.33–0.82), P=0.0053, adjusted for smoking-duration]. MDR interaction analysis showed that two the best significant models and strong synergy between MDM2 and TP53.ConclusionsMDM2 five-htSNPs haplotype exhibited association with lung cancer susceptibility, interaction of MDM2 and TP53 htSNPs and smoking-duration contributed to lung cancer risk and strong synergy between MDM2 and TP53 htSNPs influenced lung cancer predisposition. Our results suggest that MDM2, TP53 and smoking-duration interact in relation to lung carcinogenesis.

Collagen type VI \u03b15 gene variations may predict the risk of lung cancer development in Chinese Han population

The abundant expression of collagen type VI α5 (COL6A5) exists in lung tissue, and its role in lung cancer is still unknown. We performed a genetic association study with an attempt to detect the relationships between single nucleotide polymorphisms (SNPs) in COL6A5 and lung cancer predisposition in Chinese Han population. We finally selected six tag-SNPs to determine their genotypes among 510 lung cancer patients and 495 healthy controls with the MassARRAY platform. The associations of SNPs and lung cancer risk were estimated by logistic regression method with adjustment for confounding factors. Two available databases were used for gene expression and prognosis analysis. COL6A5 rs13062453, rs1497305, and rs77123808 were significantly associated with the risk of lung cancer in the whole population or stratified subgroups (p < 0.05). Among them, COL6A5 rs13062453 and rs1497305 were also linked to the susceptibility of lung adenocarcinoma. Additionally, rs1497305 was found to be strongly related to the TNM staging under five genetic models (p < 0.05). Results from databases suggested the important role of COL6A5 in lung cancer development. COL6A5 polymorphisms rs13062453, rs1497305 and rs77123808 were associated with lung cancer risk in Chinese Han population. These findings first yield new insight of COL6A5 in lung cancer.

1906P - Lung cancer predisposition in women with previous breast cancer identified by whole exome sequencing

1906P - Lung cancer predisposition in women with previous breast cancer identified by whole exome sequencing

Abstract A07: Alterations in G2/M phase associated transcriptional networks highlight lung cancer predisposition in COPD patients

Abstract Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lung cancer. COPD, clinically defined by reduced lung function measurements, is characterized by chronic airway inflammation, remodeling and loss as well as destruction of alveoli (emphysema). While this disease is an important lung cancer risk factor independent of smoking, the molecular progression from COPD to lung cancer tumourigenesis is relatively understudied. Method: We first analyzed small-airway epithelial gene expression profiles obtained from bronchial brushings from 127 COPD and 140 non-COPD ever-smoker patients. We performed weighted gene correlation network analysis (WGCNA) on these gene expression profiles to discover deregulated gene modules (“metagenes”) associated with reduced lung function (Forced Expiratory Volume at 1 second, FEV-1)—a clinical measure of COPD severity most robustly negatively correlated with lung cancer risk. We then assessed the preservation of these modules in two non-small cell lung cancer (NSCLC) tumor/normal data sets (lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), n= 887 tumors total) to examine the molecular overlap between COPD and lung cancer. Airway and tumor patient cohorts were matched for age, gender, tumor stage, and smoking status. Result: We discovered 10 distinct small-airway gene expression modules, two of which were significantly negatively correlated (p &amp;lt; 0.05) with patient FEV-1. One of these FEV-1 modules was the top overall module preserved in both NSCLC subtypes. This lung cancer-FEV-1 module contained 31 genes solely enriched for two related mitotic functions—G2/M phase transition (BH-p = 0.02) and mitotic roles of polo-like kinase (BH-p = 0.001, n=31). Of these, 28 genes were significantly overexpressed in both LUAD and LUSC, and mapped to a highly clustered sub-network of 23 proteins with 465 known and in silico-predicted protein-protein interactions. When tumors enriched for this lung cancer-FEV-1 gene signature were further examined, we observed a significant co-occurrence of DNA-level alterations in DNA damage-associated checkpoints, specifically mutated TP53. Conclusion: Coordinated gene expression changes associated with COPD severity measures in small airways and preserved in NSCLC tumors are enriched for G2/M phase transition genes. These genes are further disrupted in tumors, where co-occurring mutations to gatekeeper genes are present. Progression of mitosis during abnormal aneuploidy in lung tissues of COPD patients may confer increased risk of oncogenic transformation in this population, and may underlie the molecular progression from COPD to lung cancer. Citation Format: Erin A. Marshall, Emily A. Vucic, Victor D. Martinez, Raymond T. Ng, Wan L. Lam. Alterations in G2/M phase associated transcriptional networks highlight lung cancer predisposition in COPD patients [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A07.

Functional Polymorphism in the MSI1 Gene Promoter Confers a Decreased Risk of Lung Cancer in Chinese by Reducing MSI1 Expression.

Background: Musashi1 (MSI1) is a characteristic stem cell marker that regulates the balance between cell self-renewal and differentiation. Evidence has identified MSI1 as a pivotal oncogenic regulator in diverse malignancies. However, little evidence uncovers the role of genetic variations of MSI1 gene in cancer etiology.Objective: The aim of this study was to investigate the association between genetic variants in the MSI1 gene and lung cancer risk.Methods: Based on a two-stage retrospective study with a total of 1559 patients with lung cancer and 1667 healthy controls, we evaluated the relevance between three putative functional SNPs in the MSI1 promoter (i.e., -2696T>C[rs7959801], -2297T>C[rs3742038] and -1081C>T[rs34570155]) and lung cancer risk.Results: We found that the SNP rs7959801T>C was significantly associated with lung cancer susceptibility. Compared to those with rs7959801TT wild-genotype, individuals with CT/CC variant genotypes exerted consistently beneficial roles in lung cancer risk in the discovery set (adjusted odd ratios [OR] = 0.67; 95% confidence interval [CI] = 0.57-0.80), and in the validation set (OR=0.69; 95%CI=0.54-0.88). Functional assays indicated that the allele transformation from T to C in rs7959801 of MSI1 gene arrestingly decreased its transcription activity in vitro. Furthermore, the expression levels of MSI1 were significantly lower in the patients with CT/CC variants than in those who were with TT genotype.Conclusion: Our findings suggested that the rs7959801T>C polymorphism in the MSI1 promoter conferred a decreased risk to lung cancer by reducing the expression of MSI1 and it may be a promising indicator for lung cancer predisposition.

Role of Sequence Variations in AhR Gene Towards Modulating Smoking Induced Lung Cancer Susceptibility in North Indian Population: A Multiple Interaction Analysis.

Background: AhR, a ubiquitously expressed ligand-activated transcription factor, upon its encounter with the foreign ligands activates the transcriptional machinery of genes encoding for bio-transformation enzymes like CYP1A1 hence, mediating the metabolism of Poly aromatic hydrocarbons and nitrosamines which account for the maximally found carcinogen in cigarette smoke. Polymorphic variants of AhR play a significant role and are held responsible for disposing the individuals with greater chances of acquiring lung cancer.Objective: To study the role of AhR variants (rs2282885, rs10250822, rs7811989, rs2066853) in affect-ing lung cancer susceptibility.Methods: 297 cases and 320 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used. To analyze high order in-teractions Multifactor Dimensionality Reduction and Classification and regression tree was used.Results: Subjects carrying the variant genotype for AhR rs7811989 showed a two-fold risk (p=0.007) and a marginal risk was also seen in case of individuals carrying either single or double copy of suscep-tible allele for rs102550822 (p=0.02). Whereas the variant allele for rs2066853 showcased a strong pro-tective effect (p=0.003). SQCC individuals with mutant genotype of rs2066853 also exhibited a protec-tive effect towards lung cancer (OR=0.30, p=0.0013). The association of rs7811989 mutant genotype and rs10250822 mutant genotype was evident especially in smokers as compared to non-smokers. AhR rs2066853 showed a decreased risk in smokers with mutant genotype (p=0.002). MDR approach gave the best interaction model of AhR rs2066853 and smoking (CVC=10/10, prediction error=0.42).Conclusion: AhR polymorphic variations can significantly contribute towards lung cancer predisposi-tion.

Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians

IntroductionCancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer Methods237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. ResultsIn the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients ConclusionThrough the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.

Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.

Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.

Association of polymorphisms in Dickopff (DKK) gene towards modulating risk for lung cancer in north Indians.

To investigate the association between the genetic variants of DKK4 (rs2073664), DKK3 (rs2291599, rs3206824 and rs7391689) and DKK2 (rs447372, rs419558 and rs17037102) and lung cancer predisposition in north Indians. A total of 600 subjects were genotyped using PCR restriction fragment length polymorphism technique. Association analysis was carried out using logistic regression approach. DKK3 rs7396187 showed a protective effect (p = 0.01). Subjects with heterozygous genotype of DKK2 rs17037102 and rs419558 showed an increased risk. The variant genotype of the genotypic combination, DKK3 rs3206824 and DKK2 rs419558 showed a twofold increased risk (p = 0.008). Lung cancer risk increased four-times in subjects with variant genotype of all the three DKK2 variants. DKK2 is certainly playing a crucial role in modulating cancer susceptibility.

Evidence for a genetical contribution to non-smoking-related lung cancer

BackgroundThe majority of lung cancers are smoking-related, with environmental and genetical factors contributing. The interplay between environmental and genetical contributions in non-smoking-related lung cancers is less clear.MethodsWe analysed a population-based...

Abstract 1298: Evidence for a genetic contribution to non-smoking-related lung cancer

Abstract Introduction: Familial clustering of lung cancer has long been noted; multiple genetic analyses of lung cancer pedigrees have been performed in search of lung cancer predisposition genes. Because smoking is also observed to cluster in families, this major environmental risk factor can confound any evidence for a genetic contribution to lung cancer. We show evidence that a genetic contribution appears likely to contribute to non-smoking-related lung cancer. Data and Methods: Using a population-based resource consisting of the computerized genealogy of the Utah pioneer founders and their descendants linked to a statewide cancer registry from 1966, we have analyzed the clustering of lung cancer cases among close and distant relatives. Using linked death certificate data that includes data on the contribution of tobacco to death, the subset of deceased lung cancer cases was stratified into smoking- (n=1895) and non-smoking-related (n=784) subsets. A test for a significant excess of pairwise relatedness among all cases was performed by comparing the average relatedness of these two independent subsets of lung cancer cases to the expected relatedness in the Utah population based on analysis of matched control sets (the well-published GIF method was used). Results: Significant evidence for overall excess pairwise relatedness was observed for the 784 lung cancer cases whose death certificate stated that tobacco did not contribute to death (p= 0.001). These results suggest familial clustering, but cannot discriminate between genetic- or environmental-based clustering. To remove any effect of a familial smoking effect that is not genetic, all pairwise relationships closer than third-degree were ignored; significant excess relatedness was still observed among non-smoking cases (p=0.019). When a similar analysis was performed for lung cancer cases whose death certificate indicated a contribution to death from tobacco (n=1895), overall significant excess relatedness was observed (p&amp;lt;0.001), suggesting familial clustering of cases; however, when close relationships were ignored there was no longer evidence for significant excess relatedness (p=0.271). Conclusions: Using published methods to analyze a powerful resource linking cancer data to genealogy we have shown that while lung cancers do appear to cluster in families, there are two distinct subsets of cases. The familial clustering of those cases who do not smoke provides strong evidence for a genetic contribution, while the familial clustering of those lung cancer cases who smoke appears to resemble the clustering expected with the shared environmental risk factor of smoking. Gene identification efforts should focus on the subset of lung cancer pedigrees representing cases for whom smoking did not contribute to lung cancer. Citation Format: Lisa A. Cannon-Albright, Shamus Carr, Wallace Akerley. Evidence for a genetic contribution to non-smoking-related lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1298. doi:10.1158/1538-7445.AM2014-1298