Predicted gene expression in ancestrally diverse populations leads to discovery of susceptibility loci for lifestyle and cardiometabolic traits.

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB50k) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB50k, demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB50k analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression.

Genetic analyses of diverse populations improves discovery for complex traits.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.

BACKGROUND: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. RESULTS: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. CONCLUSIONS: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia.

ß-thalassemia (ß-Thal) is caused by defective ß-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of ß-thalassemia intermedia. In the absence of these transporters, the anemia of ß-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of ß-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved ß-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of ß-thalassemia.

Combined genetic disruption of K-Cl cotransporters and Gardos channel KCNN4 rescues erythrocyte dehydration in the SAD mouse model of sickle cell disease.

Excessive red cell dehydration contributes to the pathophysiology of sickle cell disease (SCD). The densest fraction of sickle red cells (with the highest corpuscular hemoglobin concentration) undergoes the most rapid polymerization of deoxy-hemoglobin S, leading to accelerated cell sickling and increased susceptibility to endothelial activation, red cell adhesion, and vaso-occlusion. Increasing red cell volume in order to decrease red cell density can thus serve as an adjunct therapeutic goal in SCD. Regulation of circulating mouse red cell volume and density is mediated largely by the Gardos channel, KCNN4, and the K-Cl cotransporters, KCC3 and KCC1. Whereas inhibition of the Gardos channel in subjects with sickle cell disease increased red cell volume, decreased red cell density, and improved other hematological indices in subjects with SCD, specific KCC inhibitors have not been available for testing. We therefore investigated the effect of genetic inactivation of KCC3 and KCC1 in the SAD mouse model of sickle red cell dehydration, finding decreased red cell density and improved hematological indices. We describe here generation of mice genetically deficient in the three major red cell volume regulatory gene products, KCNN4, KCC3, and KCC1 in C57BL6 non-sickle and SAD sickle backgrounds. We show that combined loss-of-function of all three gene products in SAD mice leads to incrementally increased MCV, decreased CHCM and % hyperchromic cells, decreased red cell density (phthalate method), increased resistance to hypo-osmotic lysis, and increased cell K content. The data show that combined genetic deletion of the Gardos channel and K-Cl cotransporters in a mouse SCD model decreases red cell density and improves several hematological parameters, supporting the strategy of combined pharmacological inhibition of these ion transport pathways in the adjunct treatment of human SCD.

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

Breastfeeding associated with higher lung function in African American youths with asthma.

OBJECTIVE: In the United States, Puerto Ricans and African Americans have lower prevalence of breastfeeding and worse clinical outcomes for asthma compared with other racial/ethnic groups. We hypothesize that the history of breastfeeding is associated with increased forced expiratory volume in 1 second (FEV1) % predicted and reduced asthma exacerbations in Latino and African American youths with asthma. METHODS: As part of the Genes-environments & Admixture in Latino Americans (GALA II) Study and the Study of African Americans, asthma, Genes & Environments (SAGE II), we conducted case-only analyses in children and adolescents aged 8-21 years with asthma from four different racial/ethnic groups: African Americans (n = 426), Mexican Americans (n = 424), mixed/other Latinos (n = 255), and Puerto Ricans (n = 629). We investigated the association between any breastfeeding in infancy and FEV1% predicted using multivariable linear regression; Poisson regression was used to determine the association between breastfeeding and asthma exacerbations. RESULTS: Prevalence of breastfeeding was lower in African Americans (59.4%) and Puerto Ricans (54.9%) compared to Mexican Americans (76.2%) and mixed/other Latinos (66.9%; p < 0.001). After adjusting for covariates, breastfeeding was associated with a 3.58% point increase in FEV1% predicted (p = 0.01) and a 21% reduction in asthma exacerbations (p = 0.03) in African Americans only. CONCLUSION: Breastfeeding was associated with higher FEV1% predicted in asthma and reduced number of asthma exacerbations in African American youths, calling attention to continued support for breastfeeding.

Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies.

RATIONALE: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. OBJECTIVES: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. METHODS: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 µm and ≤2.5 µm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. MEASUREMENTS AND MAIN RESULTS: A 5 µg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 µm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. CONCLUSIONS: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.

Clinical characteristics of asthmatic patients with influenza-like illness and risk of severe exacerbations in Mexico.

BACKGROUND: Patients with chronic inflammatory lung diseases, such as asthma, are at higher risk for influenza-like illness (ILI) complications. Viral infections are known to trigger asthma exacerbations, but a thorough description of the clinical characteristics of ILI-associated asthma exacerbations and the role of viruses as a risk factor for severe exacerbation (SE) in ILI has not been published yet. OBJECTIVE: To investigate risk factors for SE in patients with ILI and asthma. METHODS: Patients with ILI symptoms were recruited from 6 hospitals of Mexico (LaRed sites) during 2010 to 2014. Those with a previous asthma diagnosis and ILI symptoms and who were 5 years or older were included. Patients were assigned as cases or controls based on symptoms reported. SE was defined when participants presented with wheezing or dyspnea and required hospitalization. RESULTS: A total of 486 patients with ILI and a diagnosis of asthma were included. There were no differences in the proportion, number, or type of viral illness among those with and without SE. Those with SE were less likely to report ILI symptoms. Muscle pain and nasal drip were predictors for patients not progressing to SE. A delay in seeking medical care was associated with SE (odds ratio, 2.93; 95% CI, 1.46-5.88). CONCLUSION: The presence of a particular virus did not predict SE. ILI symptoms in asthma patients are not associated with severe exacerbation. Patients with asthma should be encouraged to seek early medical care when ILI symptoms are first noticed to prevent serious complications.

Genetic ancestry influences asthma susceptibility and lung function among Latinos.

BACKGROUND: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. OBJECTIVE: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. METHODS: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. RESULTS: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively). CONCLUSION: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos.

BACKGROUND: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders. OBJECTIVE: We sought to identify genetic variants associated with IgE levels in Latinos. METHODS: We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies. RESULTS: We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011). CONCLUSION: We confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies.

RATIONALE: Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications. OBJECTIVES: To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions. METHODS: This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO2), sulfur dioxide, particulate matter not greater than 10 µm in diameter, and particulate matter not greater than 2.5 µm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant. MEASUREMENTS AND MAIN RESULTS: After adjustment for confounders, a 5-ppb increase in average NO2 during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31). CONCLUSIONS: Early-life NO2 exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.

Completeness of Resection and Long-Term Survival of Patients Undergoing Resection for Pathologic T3 NSCLC: An International Association for the Study of Lung Cancer Analysis.

INTRODUCTION: Currently, tumors with different histopathologic characteristics and oncologic outcomes comprise the T3 category of the eight edition TNM classification for lung cancers. To better understand the T3 category, we evaluated completeness of resection and long-term survival in patients undergoing resection for T3 NSCLC. METHODS: The International Association for the Study of Lung Cancer 1999 to 2010 database was queried for patients with pathologic T3N0M0 NSCLC who underwent lobectomy or pneumonectomy. The primary outcome evaluated was overall survival (OS) stratified by T3 descriptors and completeness of resection. RESULTS: Of 1448 patients with T3N0M0 tumors, 1187 (82.0%) had a single descriptor defining them as T3. T3 tumors with chest wall infiltration (CWI) or parietal pleura infiltration (PL3) had the highest rates of incomplete resection (9.8% and 8.4%, respectively), and those classified as T3 by size only had the lowest rate of incomplete resection (2.9%). Individual T3 descriptors were associated with significant differences in OS (p = 0.005). When tumors with similar survival and complete resection rates were grouped, patients with T3 tumors characterized by size or the presence of a separate nodule (SN) in the same lobe had better 5-year OS than patients with tumors characterized by PL3 or CWI (size/SN 60% versus CWI/PL3 53%, p = 0.017) independent of completeness of resection. CONCLUSIONS: Significant differences in 5-year OS were associated with size, SN, PL3, or CWI T3 descriptors. Subdividing pathologic T3N0M0 tumors according to the presence or absence of CWI or PL3 may increase the prognostic accuracy of tumor staging.

The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the M Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: This study analyzed all metastatic categories of the current TNM classification of NSCLC to propose modifications of the M component in the next edition (ninth) of the classification. METHODS: A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stages IVA to IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using multivariable-adjusted Cox proportional hazards regression. RESULTS: The eighth edition M categories revealed good discrimination in the ninth edition data set. Assessments revealed that an increasing number of metastatic lesions were associated with decreasing prognosis; because this seems to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was found with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, revealed that M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems. CONCLUSIONS: These data validate the eighth edition M1a and M1b categories, which are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems).

The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Proposal for Revision of the TNM Stage Groupings in the Forthcoming (Ninth) Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The eighth edition of the TNM classification of pleural mesothelioma (PM) saw substantial changes in T and N components and stage groupings. The International Association for the Study of Lung Cancer collected data into a multinational database to further refine this classification. This ninth edition proposal incorporates changes proposed in the clinical (c)T component but not the pathologic T component, to include size criteria, and further refines TNM stage groupings for PM. METHODS: Data were submitted through electronic data capture or batch transfer from institutional databases. Survival was measured from diagnosis date. Candidate stage groups were developed using a recursive partitioning and amalgamation algorithm applied to all cM0 cases for clinical stage and subsequently for pathologic stage. Cox models were developed to estimate survival for each stage group. RESULTS: Of 3598 submitted cases, 2192 were analyzable for overall clinical stage and 445 for overall pathologic stage. Recursive partitioning and amalgamation generated survival tree on overall survival outcomes restricted to cM0, with newly proposed (ninth edition) cT and cN component-derived optimal stage groupings of stage I (T1N0), II (T1N1; T2N0), IIIA (T1N2; T2N1/2; any T3), IIIB (any T4), and IV (any M1). Although cT and pathologic T descriptors are different in the ninth edition, aligning pathologic stage groupings with clinical stage produced better discrimination than did retaining eighth edition pathologic stage groupings. CONCLUSIONS: To our knowledge, this revision of the clinical TNM classification for PM is the first to incorporate the measurement-based proposed changes in cT category. The pathologic TNM aligns with clinical TNM.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented. METHODS: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability. RESULTS: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer. CONCLUSIONS: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex.

The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.