Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma.

Objective: Solid and micropapillary pattern are highly invasive histologic subtypes in lung adenocarcinoma and are associated with poor prognosis while the biopsy sample is not enough for the accurate histological diagnosis. This study aims to assess the correlation and predictive efficacy between metabolic parameters in (18)F-fluorodeoxy glucose positron emission tomography/computed tomography ((18)F-FDG PET-CT), including the maximum SUV (SUV(max)), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and solid and micropapillary histological subtypes in lung adenocarcinoma. Methods: A total of 145 resected lung adenocarcinomas were included. The clinical data and preoperative (18)F-FDG PET-CT data were retrospectively analyzed. Mann-Whitney U test was used for the comparison of the metabolic parameters between solid and micropapillary subtype group and other subtypes group. Receiver operating characteristic (ROC) curve and areas under curve (AUC) were used for evaluating the prediction efficacy of metabolic parameters for solid or micropapillary patterns. Univariate and multivariate analyses were conducted to determine the prediction factors of the presence of solid or micropapillary subtypes. Results: Median SUV(max) and TLG in solid and papillary predominant subtypes group (15.07 and 34.98, respectively) were significantly higher than those in other subtypes predominant group (6.03 and 10.16, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for prediction of solid and micropapillary predominant subtypes [AUC=0.811(95% CI: 0.715~0.907) and 0.725(95% CI: 0.610~0.840), P<0.05]. Median SUV(max) and TLG in lung adenocarcinoma with the solid or micropapillary patterns (11.58 and 22.81, respectively) were significantly higher than those in tumors without solid and micropapillary patterns (4.27 and 6.33, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for predicting the presence of solid or micropapillary patterns [AUC=0.757(95% CI: 0.679~0.834) and 0.681(95% CI: 0.595~0.768), P<0.005]. Multivariate logistic analysis showed that the clinical stage (Stage Ⅲ-Ⅳ), SUV(max) ≥10.27 and TLG≥7.12 were the independent predictive factors of the presence of solid or micropapillary patterns (P<0.05). Conclusions: Preoperative SUV(max) and TLG of lung adenocarcinoma have good prediction efficacy for the presence of solid or micropapillary patterns, especially for the solid and micropapillary predominant subtypes and are independent factors of the presence of solid or micropapillary patterns.

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

Background: The micropapillary pattern (MIP) is recognized as a high-grade histological subtype in lung adenocarcinoma (LUAD), with its presence often indicative of a poorer prognosis. Despite distinctive molecular characteristics of MIP, there is a research gap regarding the molecular mechanisms underlying micropapillary transformation and prognosis factors for micropapillary LUAD. Methods: Surgically resected tumor samples from 101 patients with stage I-III LUAD and MIP components exceeding 30% were collected. The tumor samples were microdissected to separate MIP components from non-MIP components, and both fractions underwent RNA and DNA whole-exome sequencing (WES). The molecular profiles between MIP and non-MIP components, along with MIP-naïve LUAD tissues from an external cohort, were compared. Associations between molecular characteristics and recurrence-free survival were also assessed. Results: The genomic landscapes of MIP and non-MIP components within tumor tissues featuring MIP patterns exhibited remarkable similarity. At the transcriptomic level, MIP components displayed elevated PRB4 expression (FDR &amp;lt; 0.001), an up-regulated cell cycle pathway (P = 0.004), and reduced natural killer cell-mediated cytotoxicity (P = 0.066). Nevertheless, in comparison to MIP-naïve LUAD tissues, the MIP components showed higher chromosomal instability (P &amp;lt; 0.001) and revealed eighteen enriched somatic alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, all linked to up-regulations in cell proliferation pathways and down-regulated immune pathways. In the context of MIP transformation, shared mutations were observed in 97.8% (91/93) of patients between MIP and non-MIP components within the same tissues, suggesting a common origin. The subclonal fractions were comparable between paired MIP and non-MIP components, while a significant co-occurrence of EGFR amplification, CDKN2A deletion, and CDKN2B deletion was identified in MIP components. A comprehensive analysis combining differential gene expression and Cox analysis, employing a both-direction stepwise Akaike Information Criteria selection, identified the high expressions of five genes (GALNT4, MIAT, FOSL1, LAT2, SMN2) as adverse factors associated with the recurrence of micropapillary LUAD. Conclusions: We conducted an in-depth analysis of the molecular characteristics and transformation mechanisms of micropapillary lung adenocarcinoma, employing microdissection techniques to investigate at both genomic and transcriptomic levels within a substantial cohort, providing insights for the precision medicine of this aggressive cancer subtype. Citation Format: Kang Shao, Shugeng Gao, Fengwei Tan, Anqi Shao, Xiaoli Feng, Qi Xue, Yang Qu, Bo Zheng, Wei Zheng, Hanlin Chen, Qiuxiang Ou, Haimeng Tang. Multi-omics analysis of molecular characteristics and transformation mechanisms of stage I-III micropapillary lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6466.

Invasive adenocarcinoma subtypes are known to be associated with prognosis; however, the underlying reason remains unclear. To find out the reason, we investigated the possible influence of lymph node (LN) involvement by the constituent histologic subtypes in the tumor and clarified the different prognosis according to the predominant histologic subtypes in the tumor and LN. A total of 97 consecutive patients who underwent surgical resection for lung invasive adenocarcinoma between February 2009 and December 2015 were included. We analyzed the associations of the histologic subtypes between the tumor and LN and disease-free survival (DFS) according to the histologic subtypes and predicted the histologic subtype in LN involvement using the component ratio of the predominant histologic subtype in the tumor. A P value <0.05 was considered statistically significant. Acinar and papillary subtypes occupied the majority of the predominant histological subtypes (tumor 73.2%, LN 71.1%). The tumor showed significantly more constituent histologic subtypes than LN (P<0.001). Micropapillary and solid predominant subtype were more common in poorer differentiation (tumor P<0.001, LN P=0.001). The predominant histologic subtype in the tumor was not the same as that in LN and micropapillary and solid predominant subtypes were significantly more prone to LN involvement than other subtypes (P<0.001). Regarding the predominant histologic subtypes in the tumor, there was no significant difference in DFS between micropapillary and solid predominant subtypes and other subtypes. However, regarding the predominant histologic subtypes in LN, micropapillary and solid predominant subtypes had significantly lower DFS than other subtypes (P=0.010). Solid predominant subtype had a significant cutoff value for prediction of the predominant histologic subtype in LN using the component ratio of the predominant histologic subtype in the tumor (cutoff value 12.5%, sensitivity 70.0%, specificity 82.4%, area 0.775, P<0.001). The present study presented a possible reason of discrepancies in outcomes according to the lung adenocarcinoma constituent subtypes. Micropapillary and solid predominant subtypes had poorer prognosis than other subtypes, which might be explained by being more prone to LN involvement.

Background The volume doubling time (VDT) is a key parameter in the differentiation of aggressive tumors from slow-growing tumors. How different histologic subtypes of primary lung adenocarcinomas vary in their VDT and the prognostic value of this measurement is unknown. Purpose To investigate differences in VDT between the predominant histologic subtypes of primary lung adenocarcinomas and to assess the correlation between VDT and prognosis. Materials and Methods This retrospective study included patients who underwent at least two serial CT examinations before undergoing operation between July 2010 and December 2018. Three-dimensional tumor segmentation was performed on two CT images and VDTs were calculated. VDTs were compared between predominant histologic subtypes and lesion types by using Kruskal-Wallis tests. Disease-free survival (DFS) was obtained in patients undergoing surgical procedures before July 2017. Univariable and multivariable Cox proportional hazards regression analyses were performed to determine predictors of DFS. Results Among 268 patients (mean age, 64 years ± 8 [standard deviation]; 143 men), there were 30 lepidic, 87 acinar, 109 papillary, and 42 solid or micropapillary predominant subtypes. The median VDT was 529 days (interquartile range, 278-872 days) for lung adenocarcinomas. VDTs differed across subtypes (P < .001) and were shortest in solid or micropapillary subtypes (229 days; interquartile range, 77-530 days). Solid lesions (VDT, 248 days) had shorter VDTs than subsolid lesions (part-solid lesions, 665 days; nonsolid lesions, 648 days) (P < .001). In the 148 patients (mean age, 64 years ± 8; 89 men) included in the survival analysis, 35 patients had disease recurrence and 17 patients died. VDT (<400 days) was an independent risk factor for poor DFS (hazard ratio, 2.6; P = .01) and higher TNM stage. Adding VDT to TNM stage improved model performance (C-index, 0.69 for TNM stage vs 0.77 for combined VDT class and TNM stage; P = .002). Conclusion Volume doubling times varied significantly according to the predominant histologic subtypes of lung adenocarcinoma and had additional prognostic value for disease-free survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Ko in this issue.

Lung adenocarcinomas with micropapillary pattern (MP) or solid pattern (SP) have poor prognosis with frequent postoperative recurrence. However, treatment strategies for these histological subtypes have not been established. This study examined the recurrence rates and patterns in patients with these histological subtypes. Overall, 238 patients with lung adenocarcinoma who underwent radical resection were included. According to the histological subtypes, the patients were classified into three groups: neither MP nor SP (MP-/SP-), MP (MP+), and SP (SP+). The clinical and pathological characteristics and recurrence-free survival (RFS) were examined in each group. In addition, univariate and multivariate analyses were performed to investigate the recurrence factors. The site of recurrence, PD-L1 expression, and driver mutations were examined in patients with postoperative recurrence. The recurrence rates were significantly higher in the MP+ and SP+ groups (p = 0.01). The RFS was significantly shorter in the MP+ and SP+ groups (p < 0.001) than in the MP-/SP- group, especially in pStage 1A (p = 0.001). The relationship between recurrence and pathologic factors was significant for pleural, lymphatic, and vascular invasion, as well as MP in univariate analysis and only for MP in multivariate analysis. Most recurrences were distant metastases in the MP+ and SP+ groups. PD-L1 was highly expressed in recurrent SP+ cases. Early-stage lung adenocarcinoma with MP or SP frequently has postoperative recurrence. Prevention of distant metastases is important in these patients to improve prognosis, and aggressive postoperative chemotherapy may be considered.

OA24.06 Histologic Subtype of Early-Stage Lung Adenocarcinoma is a Predictor of Failure Patterns after Stereotactic Body Radiation Therapy

Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed. We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate. The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2cm), in predicting either predominant histology (χ2 = 7.091, P = 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (χ2 = 22.301, P < 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (χ2 = 17.560, P < 0.001 and χ2 = 61.938, P < 0.001, respectively). CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2cm) or an initially pure GGO group.

P1.05-066 Impact of Micropapillary Pattern in Nodal Upstaging of Lung Adenocarcinoma 2cm or Less

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

Background: Neoplastic progression in lung cancer often involves tumors with heterogeneous histologies, harboring multiple subclones of distinct histological subtypes - such as lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), and small cell lung carcinoma (SCLC) - within a single tumor. Determining histological subtype of the tumor typically requires invasive lung tissue biopsy, which precludes serial monitoring both during and after therapy. Treatment regimens targeting the predominant histology may inadvertently select for drug-resistant subclones of alternative subtypes, necessitating timely adjustments in treatment strategies. Comprehensive cfDNA methylation profiling across thousands of cancer-associated regulatory regions offers an approach for accurate quantification of lung cancer histological subtypes, facilitating enhanced noninvasive disease monitoring and more effective therapeutic strategies. Methods: We developed a novel cfDNA methylation-based deconvolution model to identify and quantify the proportional contributions of LUAD, LSCC and SCLC in patient blood samples. The model leverages hypermethylation signals across over 9000 of cancer-associated genomic regions to estimate the contribution of each histological subtype while simultaneously predicting patient-specific subtype hypermethylation signatures and non-cancer component signatures across regions. We modeled each sample as a linear combination of its three histological subtype and non-cancer components weighted by their proportional contributions. The model was trained using stochastic gradient descent to minimize both reconstruction and proportional contribution losses. Using samples from cancer-free individuals (N=6, 142), and lung cancer patients (LUAD N=2, 721, LSCC N=663, and SCLC N=243), the model was trained using 90% of the data and tested on the remaining 10%. For each test sample, the model was used to predict proportions of three histological subtypes summing to 100%. Model performance was evaluated by comparing the predicted histological subtypes to the known histological subtype annotations of lung cancer samples. Results: The overall accuracy on the test set was 85.1% down to 0.1% tumor fraction, with the highest accuracy for LUAD (90.4%), followed by LSCC (72.4%) and SCLC (63.5%). Importantly, the model demonstrated capability to detect minor subclonal contributions as low as 0.1%. Conclusions: Our methylation-based subtype deconvolution model provides an accurate method for quantifying proportions of lung cancer histological subtypes in patient blood samples, with the unique ability to detect minor subclonal populations. This approach enables the early non-invasive detection of treatment-resistant lung cancer subtypes, thereby holding significant potential to improve patient outcomes. Citation Format: Anton Valouev, Wei Tian, Kunwar Singh, Sheila Solomon, Justin Odegaard, Darya Chudova, Helmy Eltoukhy. Non-invasive cell free DNA (cfDNA) methylation profiling for accurate proportional quantification of lung cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1142.

Introduction: Although histological subtype in lung adenocarcinoma has been reported as a poor prognostic factor in several studies, its utility has not yet been revealed as an adaptation criterion of postoperative adjuvant chemotherapy. Methods: Four hundred ninety-four lung adenocarcinoma patients were enrolled in this retrospective study. A subanalysis was performed in 420 lung adenocarcinoma patients with pathological stage 0–I disease for risk factors of postoperative recurrence. Results: Maximum standardized uptake value (SUV_max) (p < 0.01), pathological stage ≥II (p < 0.04), and adjuvant chemotherapy (p < 0.01) were risk factors for recurrence in the multivariate analysis, whereas histological subtype was not a significant factor for recurrence at all stages. In the subanalysis, univariate analysis showed that carcinoembryonic antigen expression (p < 0.01), prognostic nutrition index (p = 0.03), SUV_max (p < 0.01), lymphatic invasion (p < 0.01), vascular invasion (p < 0.01), grade 3–4 differentiation (p < 0.01), pathological stage ≥IA3 (p < 0.01), and histological subtype (p = 0.03) were significant risk factors of recurrence. SUV_max (p < 0.01) was the only risk factor for recurrence in the multivariate analysis, whereas histological subtype was not (p = 0.07). Relapse-free survival (RFS) was significantly worse in the micropapillary- and solid-predominant subtype groups than in the other subtypes (p = 0.01). On the other hand, RFS with or without uracil-tegafur as adjuvant chemotherapy in lung micropapillary- or solid-predominant adenocarcinoma patients with pathological stage IA-IB disease was not significantly different. Conclusion: This study suggested that histological subtypes, such as micropapillary- or solid-predominant pattern, are risk factors for recurrence in pathological stage 0-I lung adenocarcinoma and may be necessary adjuvant chemotherapy instead of uracil-tegafur.

Background: We have reported DNA methylation alterations in non-cancerous lung tissue obtained from lung cancer patients. These previous data drew our attention to DNA methylation alterations at precancerous stage of lung adenocarcinoma (LADC). However, the impact of DNA methylation alterations at precancerous stage on the characteristics of established LADCs has been unclear. The purpose of this study is to clarify the significance of DNA methylation profiles during lung carcinogenesis. Methods: Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue (C), 139 samples of non-cancerous lung tissue (N) obtained from patients with LADCs, and the corresponding 139 samples of tumorous tissue (T) as a learning cohort. As a validation cohort, the 50 paired samples of N and the corresponding T were obtained from patients with primary LADCs. Results: 3,621 probes showed significant differences in DNA methylation levels between the 36 C and 139 N samples in the learning cohort, suggesting that N was at precancerous stage with DNA methylation alterations. Unsupervised hierarchical clustering using DNA methylation levels of N on 26,447 autosomal probes subclustered 139 patients of the learning cohort into Cluster A (n=32), B (n=35) and C (n=72). Most of patients in Cluster A were heavy smokers and frequently showed severe pleural anthracosis which mainly reflects smoking history. LADCs in Cluster A were locally invasive tumors which develop in emphysematous lung tissue associated with inflammation. Most of patients in Cluster B were non-smokers and LADCs in Cluster B showed less aggressive features. Most of patients in Cluster C were light smokers and LADCs in Cluster C showed more frequent lymph node metastasis and higher Tumor-Node-Metastasis (TNM) stages. The cancer-free and overall survival rates of patients in Cluster C were significantly lower than those of Cluster B. We indetified 21, 26 and 35 probes as markers which characterize Clusters A, B and C, respectively. In the validation cohort, DNA methylation levels of Cluster A, B and C marker probes were significantly correlated with pleural anthracosis, never-smoking history, and lymph node metastases and higher TNM stages, respectively, i.e. correlation between DNA methylation profiles and each clinicopathological parameter were validated in the validation cohort. Conclusion: DNA methylation profiles of Clusters A and C at precancerous stage may be established by the effects of smoking through or not thorough inflammation, respectively, whereas those of Cluster B may be associated with carcinogenesis in non-smokers. DNA methylation profiles at precancerous stage may underlie distinct pathways of lung carcinogenesis and determine tumor aggressiveness and patient outcome. Citation Format: Takashi Sato, Eri Arai, Takashi Kohno, Koji Tsuta, Shun-ichi Watanabe, Kenzo Soejima, Tomoko Betsuyaku, Yae Kanai. DNA methylation profiles at precancerous stage cluster lung adenocarcinomas into subclusters associated with carcinogenetic pathway, clinicopathological aggressiveness and patient outcome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5364. doi:10.1158/1538-7445.AM2013-5364

Lung adenocarcinoma is histologically diverse but has distinct histologic growth patterns. There is no consensus on the clinical benefit of this histologic model. We aimed to evaluate the differences in the distribution of the preoperative primary tumor positron emission tomography (PET)/computed tomography (CT) standardized uptake values (SUVs) and survival in the lung adenocarcinoma subtypes. We retrospectively evaluated the data of 107 patients with resected lung adenocarcinoma who had preoperative PET/CT between 2005 and 2017 in a single center. Patients had lepidic, acinar, papillary, micropapillary, and solid histologic subtypes. We compared fluorodeoxyglucose SUVs and survival data of histologic subtypes. The median age of the patients was 62 years (40-75), 76.4% were male, the median SUVmax was 9.4 (1-36.7), and the median follow-up time was 29 months (3-135 months). The median overall survival (OS) was 71 months and the median progression-free survival (PFS) was 33 months. SUVmax was significantly different in histologic subtypes: values for papillary, micropapillary, solid, acinar, and lepidic subtypes were 9.7, 8, 12, 9.1, and 3.9, respectively (p = 0.000). Solid predominant adenocarcinoma had significantly higher SUVmax than the other subtypes (p = 0.001). Lepidic predominant adenocarcinoma had significantly lower SUVmax than the other subtypes (p = 0.000). There was no significant difference in OS between histologic subtypes (p = 0.66), but PFS was significantly different between the groups (p = 0.017), and the solid subtype had a shorter PFS than the other histologic subtypes. Lung adenocarcinoma consists of a diverse group of diseases. Different SUVmax values are seen in different histologic subtypes of nonmetastatic lung adenocarcinoma. Solid predominant types have high SUVmax values while lepidic predominant types have lower SUVmax values. The solid subtype had a shorter PFS than the other histologic subtypes.

The aim of this study was to clarify correlations between epigenomic and genomic alterations during multistage lung adenocarcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis with the Infinium HumanMethylation27 BeadChip was performed using 162 paired samples of non-cancerous lung tissue (N) and corresponding tumorous tissue (T) from patients with lung adenocarcinomas. Correlations between DNA methylation data on the one hand and clinicopathological parameters and genomic driver mutations, i.e. mutations of EGFR, KRAS, BRAF, and HER2 and fusion involving ALK, RET, and ROS1, were examined. In N samples, which were considered to be at precancerous stages, DNA methylation levels in 12,629 probes were significantly correlated with recurrence-free survival. DNA methylation profiles at the precancerous N stages may determine the prognostic outcome. Principal component analysis revealed that distinct DNA methylation profiles at the precancerous N stage tended not to induce specific genomic driver mutations. Most of the genes showing significant DNA methylation alterations during transition from N to T were shared by two or more driver aberration groups, indicating that, in general, each driver mutation does not induce a specific DNA methylation profile. Commonly shared DNA methylation alterations which could potentially result in expression abnormalities were enriched among transcriptional factors. In contrast, only 67 genes showed EGFR mutation-specific or “pan-negative”-specific DNA methylation alterations. Among the 67 genes, most of the DNA methylation alterations were correlated with clinicopathological parameters reflecting tumor aggressiveness. We further focused on the ZNF132 gene, for which DNA hypermethylation had been observed only in the “pan-negative”-type lung adenocarcinomas and was significantly correlated with their vascular invasion. 5-aza-2'-deoxycytidine treatment restored the expression levels of ZNF132 mRNA in lung adenocarcinoma cell lines, indicating that ZNF132 had been silenced due to DNA hypermethylation. Knockdown of ZNF132 using siRNA transfection led to increased cell migration ability, rather than increased cell growth or reduced apoptosis. We concluded that DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of “pan-negative”-type lung adenocarcinomas. In addition, DNA methylation alterations at the precancerous stage may determine tumor aggressiveness, and such alterations that accumulate after driver mutation may additionally modify clinicopathological features through alterations of gene expression. Citation Format: Kenichi Hamada, Ying Tian, Mao Fujimoto, Takahashi Yoriko, Takashi Kohno, Koji Tsuta, Shun-ichi Watanabe, Teruhiko Yoshida, Hisao Asamura, Yae Kanai, Eri Arai. Correaltions between genome-wide DNA methylation profiles and genomic driver aberrations during multistage lung adenocaricinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2094.