Genie Out of the Bottle: Is There a Role for Gene-Gene Interactions in Early Detection of Lung Cancer?

Cancer continues to be a leading cause of death worldwide, with the annual number of deaths approaching 10 million.1International Agency for Research on CancerWHO. Global cancer observatory: cancer today.https://gco.iarc.fr/todayDate accessed: February , 2021Google Scholar In the past 50 years, improvements in detection, characterization, and treatment have improved outcomes for many different cancers. In the twenty-first century, much of this progress has derived from improvements in our understanding of the epidemiology of cancer and innovative approaches to screening. Expanding knowledge of cancer biology has created the opportunity for personalizing cancer care through the use of predictive biomarkers and bespoke approaches to monitoring treatment response. Understanding the molecular and biological diversity of individual persons can greatly accelerate this progress. The ability to identify individuals who are most likely to develop cancer is an opportunity that may lie within reach. From the first discovery of the structure of DNA in 1953, to the success of the Human Genome Project in the 1990s, to the state-of-the-art genome-wide sequencing of today, our ability to measure and quantify human genetic material has improved at an exponential rate.2Watson J. Crick F. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid.Nature. 1953; 171: 737-738Crossref PubMed Scopus (8259) Google Scholar,3Collins F.S. McKusick V.A. Implications of the human genome project for medical science.JAMA. 2001; 5: 540-544Crossref Scopus (556) Google Scholar These technologic advances deliver enormous amounts of genetic data, some of which have been used to identify germline mutations, which are associated with 5% to 10% of all cancers, and somatic mutations that drive many other cancers.4National Cancer InstituteThe genetics of cancer.https://www.cancer.gov/about-cancer/causes-prevention/geneticsDate accessed: May 24, 2022Google Scholar Nevertheless, understanding potentially causal associations from genetic information is difficult. Harnessing genetic information to improve risk assessment and curative treatments requires many different types of data evaluation. Patients with cancer are often tested for specific somatic driver mutations by single mutation tests, multiplex panel tests that evaluate several genes with immediate therapeutic implications, or more comprehensively, next-generation sequencing. Whole genome sequencing is also available but conducted on nontumor cells among individuals with and without cancer. This sequencing translates all DNA base pairs, reporting single nucleotide polymorphisms (SNPs), which cover a large percentage of the individual’s genome, and DNA methylation, both of which are then evaluated for potential associations with cancer.5Takeshima H. Ushijima T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk.npj Precis Oncol. 2019; 3: 7Crossref PubMed Scopus (88) Google Scholar This genome-wide SNP information has led to gene-by-gene (G×G) interaction studies to evaluate how the presence or absence of two SNP combinations may work together to increase or decrease the probability of developing a certain type of cancer.6Li Y. Xiao X. Bossé Y. et al.Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.Oncotarget. 2019; 10: 1760-1774Crossref PubMed Scopus (13) Google Scholar Despite the massive number of SNPs, genes, and mutations found to have some association with cancer, the utility of genetic information in lung cancer is somewhat limited. Most progress in using genetic information to improve lung cancer care has been in the development of genetically targeted therapy. As of May 2022, nine tumor driver mutations have U.S. Food and Drug Administration–approved targeted therapies available to patients with lung cancer. Nevertheless, besides prevention, early detection remains the most impactful way to reduce cancer mortality. Compared with developments in therapy, there has been little progress using genetic information to identify persons at risk for future development of cancer. The utility of this approach is illustrated by the role of germline BRCA1 and BRCA2 mutations in breast and ovarian cancers.4National Cancer InstituteThe genetics of cancer.https://www.cancer.gov/about-cancer/causes-prevention/geneticsDate accessed: May 24, 2022Google Scholar As impressive as is the potential population-level impact of lung cancer screening, current eligibility criteria, based on age and cigarette smoking history, pose a major barrier to access and effectiveness. For example, smoking history is notoriously difficult to accurately quantify; smoking-related lung cancer risk varies by sex and race.7Haiman C.A. Stram D.O. Wilkens L.R. et al.Ethnic and racial differences in the smoking-related risk of lung cancer.N Engl J Med. 2006; 354: 333-342Crossref PubMed Scopus (570) Google Scholar These criteria have led to notable disparities in age and smoking history-based eligibility for early detection.8Pinsky P.F. Lau Y.K. Doubeni C.A. Potential disparities by sex and race or ethnicity in lung cancer screening eligibility rates.Chest. 2021; 160: 341-350Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,9Aldrich M.C. Mercaldo S.F. Sandler K. Blot W.J. Grogan E.L. Blume J.D. Evaluation of USPSTF lung cancer screening guidelines among African American adult smokers.JAMA Oncol. 2019; 5: 1318-1324Crossref PubMed Scopus (88) Google Scholar Furthermore, depending on the population, 15% (Western populations) to more than 90% (Asian women) of persons with lung cancer may never have smoked cigarettes. Lung cancer in individuals who never smoked cigarettes would be among the top 10 most common cancers, yet all such individuals are currently ineligible for screening by most existing criteria. Compared with breast cancer and prostate cancer, only a small proportion of patients with lung cancer are identified through screening. Efforts to promote guideline-concordant management of incidentally detected pulmonary nodules may expand access to early lung cancer detection.10Osarogiagbon R.U. Liao W. Faris N.R. et al.Lung cancer in persons participating in screening, lung nodule program and neither: a prospective observational study of the detecting early lung cancer (DELUGE) in the Mississippi Delta cohort.J Clin Oncol. 2022 Jul 1; 40 (https://doi.org/10.1200/JCO.21.02496. Epub 2022 Mar 8.): 2094-2105Crossref PubMed Scopus (5) Google Scholar,11Rivera M.P. Cupertino P. Henderson L.M. Complementary approaches to lung cancer detection in high-risk populations.J Clin Oncol. 2022; 40: 2074-2077Crossref PubMed Scopus (2) Google Scholar Such Incidental Lung Nodule Programs highlight the need to move beyond current age and smoking history-based screening eligibility criteria.10Osarogiagbon R.U. Liao W. Faris N.R. et al.Lung cancer in persons participating in screening, lung nodule program and neither: a prospective observational study of the detecting early lung cancer (DELUGE) in the Mississippi Delta cohort.J Clin Oncol. 2022 Jul 1; 40 (https://doi.org/10.1200/JCO.21.02496. Epub 2022 Mar 8.): 2094-2105Crossref PubMed Scopus (5) Google Scholar Risk calculators, which include additional variables beyond age and smoking history, may incrementally improve patient selection, but their use remains fraught with challenges. Leveraging genetic information to improve lung cancer risk prediction and early detection may be a “moonshot” approach that will require collection and analysis of large, multiethnic data sets. In this edition of the Journal of Thoracic Oncology, Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar report results from one of the first studies evaluating associations between G×G interactions and risk of NSCLC. The authors used a multistage approach, starting by evaluating a large sample of (445,221) individuals of European descent.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar In the first stage of the analysis, Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar identified two G×G interactions that were significantly associated with lung cancer in a two-phase study among Europeans. They then identified six more significant G×G interactions with meta-analysis among Europeans. In total, eight SNP pairs had interactions that were associated with lung cancer. Notably, these eight SNP pairs were predominantly found in two regions (6p21.32 and 5p15.33). In the second stage of the analysis, Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar conducted a validation study in a sample of Han Chinese individuals. The sample included 10,248 individuals with, and 9298 without, lung cancer. Although the method used by the authors for the second stage, which is well described in the publication, differed slightly from the first stage, the overall approach was consistent. In this evaluation, three pairs of SNPs in the 6p21.32 region previously identified from the European ancestry population remained significant among the Asian population. On the basis of the G×G interactions identified in these two cohorts, Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar updated lung cancer screening models based on polygenetic risk scores for individuals who smoked and those who did not. They developed the interaction-empowered polygenetic risk score using the UK Biobank data set. The risk scores from this model classify individuals in deciles, identifying a subgroup who might be at high risk for developing lung cancer. The natural application of such findings lies at the point of early detection, so the authors conclude that the significant G×G interactions identified in the 5p15.33 and 6p21.32 regions may enhance lung cancer screening models. This work by Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar is a step toward more sophisticated use of genetic information for early lung cancer detection. But how practical is this approach? Generating scientific knowledge is a necessary first step, but successful implementation of well-designed interventions is needed to make an impact on patient outcomes. Uptake of both lung cancer screening and molecular testing of lung cancer has been suboptimal.13Fedewa S.A. Kazerooni E. Studts J.L. et al.State variation in low-dose computed tomography scanning for lung cancer screening in the United States.J Natl Canc Inst. 2021; 113: 1044-1052Crossref PubMed Scopus (50) Google Scholar, 14Mileham K.F. Schenkel C. Bruinooge S.S. et al.Defining comprehensive biomarker-related testing and treatment practices for advanced non-small-cell lung cancer: results of a survey of U.S. oncologists.Cancer Med. 2022; 11: 530-538Crossref PubMed Scopus (4) Google Scholar, 15Fox A.H. Jett J.R. Roy U.B. et al.Knowledge and practice patterns among pulmonologists for molecular biomarker testing in advanced non-small cell lung cancer.Chest. 2021; 160: 2293-2303Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 16Smeltzer M.P. Wynes M.W. Lantuejoul S. et al.The International Association for the Study of Lung Cancer (IASLC) global survey on molecular testing in lung cancer.J Thorac Oncol. 2020; 15: 1434-1448Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Globally, most clinicians believe that less than half of patients with lung cancer undergo any molecular testing and are not satisfied with the state of molecular testing in lung cancer.16Smeltzer M.P. Wynes M.W. Lantuejoul S. et al.The International Association for the Study of Lung Cancer (IASLC) global survey on molecular testing in lung cancer.J Thorac Oncol. 2020; 15: 1434-1448Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Key barriers that have been reported include awareness, access, cost, quality of testing, and turnaround time.16Smeltzer M.P. Wynes M.W. Lantuejoul S. et al.The International Association for the Study of Lung Cancer (IASLC) global survey on molecular testing in lung cancer.J Thorac Oncol. 2020; 15: 1434-1448Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Health care system-level logistical concerns must be addressed such as who provides this service, how long does it take, and who covers the costs. Concerns about understanding and interpreting findings also present barriers to molecular testing. Large as these barriers are for individuals who have been diagnosed with lung cancer, they may be even greater for individuals without lung cancer, in whom the objective is to assess future risk. Implementation of risk-based screening for lung cancer has been inhibited by system-, provider-, and patient-level barriers. Comprehensive lung-screening programs require substantial institutional investment in infrastructure, manpower, and care coordination processes; primary care providers face barriers such as complex and shifting eligibility criteria, nihilism about lung cancer, additional requirements for shared decision-making and tobacco counseling, and fragmented health care coverage policies.17Coughlin J.M. Zang Y. Terranella S. et al.Understanding barriers to lung cancer screening in primary care.J Thorac Dis. 2020; 12: 2536-2544Crossref PubMed Scopus (18) Google Scholar Patients are frequently unaware of the benefits and availability of lung cancer screening and may be reluctant to undergo screening because of fear of possible findings and tobacco-related stigma.18Kirby T. Reducing stigma around smoking would encourage more early lung cancer screening.Lancet Respir Med. 2020; 8: 140Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Implementation of tools for assessing genetic risk for lung cancer will likely face the combination of barriers to screening and molecular testing. The slow uptake of biomarker testing likely presages the pace of uptake of gene-based lung cancer risk assessment. Knowledge dissemination, cost, coordination challenges, and lung cancer-associated nihilism and stigma are likely to be major barriers, especially in the community practice setting. Patients and providers will need to be educated on the utility of genetic screening and how results can be incorporated into existing workflows and decision-making. The full ramifications of using genetics to predict future risk for life-threatening illness is an ethical quandary that will need careful negotiation. Great care must be taken to avoid stigmatization. The approach to handling other, non–lung cancer-related genomic findings will need to be determined. The future holds great promise for incorporating genetics across the spectrum of lung cancer, from risk prediction, early detection, to diagnosis, staging, treatment, and survivorship care for individuals with early- and late-stage lung cancer. The work by Zhang et al.12Zhang R. Shen S. Wei Y. et al.A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians.J Thorac Oncol. 2022; 17: 974-990Abstract Full Text Full Text PDF Scopus (4) Google Scholar glances at the possibility of using genetic information for early lung cancer detection. The lung cancer community should embrace this possibility in a patient-centered, evidence-driven way. Matthew Smeltzer, Meredith Ray, Nicholas Faris: Conceptualization, Writing—original draft, Writing—review and editing. Raymond Osarogiagbon: Conceptualization, Writing—original draft, Writing—review and editing, Funding acquisition. This study was funded by National Cancer Institute R01 CA172253 (Dr. Osarogiagbon). A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in AsiansJournal of Thoracic OncologyVol. 17Issue 8PreviewAlthough genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). Full-Text PDF Open Access