Concurrent mutations in multiple tumor suppressor genes correlate with adverse prognosis in stage I lung adenocarcinoma patients

Introduction

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and a leading cause of cancer-related mortality worldwide (1,2). Although most LUAD cases are diagnosed at an advanced stage with poor prognosis (3-5), 11.8% to 31.3% of early-stage patients remain at high risk of recurrence even after surgical treatment, substantially affecting long-term survival. Current treatment primarily involves surgery and postoperative follow-up, with limited application of neoadjuvant therapy, leaving a gap in strategies to reduce recurrence in stage I LUAD patients.

While clinical, pathological, and imaging factors have been studied as recurrence risk indicators, molecular-level understanding, particularly regarding multi-gene co-mutations, remains limited. TP53, a key tumor suppressor gene (TSG), plays a critical role in cell cycle regulation, DNA repair, and apoptosis (6), and its mutations are significant drivers in the occurrence and progression of lung cancer (7,8). However, TP53 mutations alone incompletely explain the heterogeneity of LUAD. Other TSGs such as BRCA1, PTEN, NF1 and STK11 are also implicated in LUAD progression and poor prognosis (9-12). Emerging evidence suggests that co-mutations of multiple TSGs may synergistically worsen prognosis (13,14). Nevertheless, most studies in stage I LUAD focus on single-gene mutations, and the role of TP53 co-mutations with other TSGs remains inadequately explored.

This study aimed to elucidate the relationship between various TP53/TSG statuses and the clinical, imaging, pathological, and genetic characteristics of stage I LUAD patients, focusing on the impact of TP53/TSG co-mutations on prognosis. Our findings may provide more precise treatment and follow-up management strategies for surgically treated stage I LUAD patients, particularly those harboring co-mutations. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-29/rc).

Methods

Study population

This retrospective study included 754 patients with pathologically confirmed stage I (T1a-2aN0M0) lung cancer, all of whom had undergone genetic testing and were treated at West China Hospital of Sichuan University between 2016 and 2019. After applying inclusion and exclusion criteria (Figure 1), a total of 618 patients were ultimately included in the study. Clinical data collected included demographic information (sex, age), smoking history, family history of tumors, personal history of tumors, surgical approaches, and whether postoperative adjuvant therapy was administered. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of West China Hospital of Sichuan University [approval No. 2024(2413)], with a waiver for written informed consent.

Figure 1 The workflow chart for inclusion and exclusion criteria. TSG, tumor suppressor gene.

Imaging and pathological data

All cases underwent high-resolution thin-slice computed tomography within three months prior to surgery, with images reviewed by two experienced chest subspecialty radiologists with more than 5 years of experience. Pathological examination of surgically resected tissue was used as the gold standard for tumor characterization, with pathological staging performed according to the 8th edition of the tumor, node, metastasis (TNM) staging system (15).

Gene mutation detection and grouping

Gene sequencing was conducted using a 56-gene panel via next-generation sequencing (see Table S1). Patients were categorized into three groups based on mutation status: the TP53+/TSG+ group, with mutations in both TP53 and any other TSG (BRCA1, BRCA2, PTEN, NF1, STK11, ATM, CDKN2A, TSC1, TSC2); the TP53+/TSG− group, with mutations in TP53 only; and the TP53− group, with no TP53 mutations.

Postoperative follow-up

Follow-up data were primarily obtained through patient visits to our Thoracic Surgery/Lung Cancer Center outpatient clinic. Patients were followed every six months for the first three years postoperatively and annually thereafter. For those followed at local healthcare facilities, data were collected via telephone. Recurrence-free survival (RFS) was defined as the time from surgery to the first recurrence, confirmed by imaging or pathology. Local relapse included recurrence in the ipsilateral lymph nodes, bronchial stump, pleura, or chest wall, while distant recurrence involved metastasis to the contralateral lung, liver, brain, or other organs (16).

Public database collection

Clinical and somatic mutation data from the Memorial Sloan Kettering (MSK) cohort were obtained from the cBioPortal website (https://www.cbioportal.org) for cancer genomics research (17). All patients in this dataset with pathologically confirmed stage I LUAD underwent complete resection and next-generation targeted sequencing.

Statistical methods

Statistical analysis was performed using R software (version 4.3.1). Quantitative data were expressed as medians [min, max] and compared using the Kruskal-Wallis H test. Categorical data were expressed as proportions and compared using the chi-square test or Fisher’s exact test. RFS was estimated by the Kaplan-Meier method, with significance determined by the log-rank test. Bonferroni correction was applied for post-hoc multiple comparisons. Independent prognostic factors were identified using the Cox proportional hazards regression model, providing hazard ratios (HRs) and 95% confidence intervals (CIs). The “muhaz” package was used for hazard function estimation to describe changes in recurrence risk over time (18). All P values were two-tailed, with P<0.05 considered statistically significant.

Results

Clinical characteristics of patients

A total of 618 patients with completely resected stage I LUAD were included: 402/618 (65.0%) were female, 511/618 (82.7%) were non-smokers, and the median age was 55 [29, 84] years (Table 1). Although there were age differences between the groups (P=0.04), post-hoc comparisons revealed no statistically significant differences. The proportions of males and individuals with a smoking history were higher in patients with TP53 mutations compared to those with wild-type TP53 (all P<0.001). Lobectomy was performed in 57.0% of cases, and sublobar resection in 43.0%, and 8.7% of patients received postoperative adjuvant therapy, with a higher proportion of TP53 mutation-positive patients receiving such therapy. Stage I LUAD patients had a high EGFR mutation rate (383/618, 62.0%), followed by TP53 (130/618, 21.0%), ERBB2 (52/618, 8.4%), KRAS (39/618, 6.3%), ALK (28/618, 4.5%), and others (Table S2). Interestingly, EGFR mutations frequently co-occurred with TP53 mutations, while co-existence with other TSG mutations was less common in TP53 mutation-positive patients.

Imaging and pathological characteristics under different TP53/TSG statuses

Imaging revealed that most tumors had subsolid density and appeared as nodules. Tumors ≤30 mm and with subsolid density were more frequent in the TP53− group than in the TP53+ group, regardless of TSG status (all P<0.05). Imaging characteristics showed high rates of spiculation (51.8%), lobulation (37.1%), and pleural indentation (33.5%), with fewer cases of vacuole formation (4.0%). Spiculation and pleural indentation were more prevalent in the TP53+/TSG+ and TP53+/TSG− groups than in the TP53− group (all P<0.05), though differences between the TP53+/TSG+ and TP53+/TSG− groups were not statistically significant (all P>0.05). Pathologically, almost no tumors showed lympho-vascular invasion (LVI) or perineural invasion, while visceral pleural invasion (VPI) was reported in 17.2% of patients (106/618). VPI was more common in the TP53+ groups than in the TP53− group (all P<0.05) and was highest in the TP53+/TSG+ group (Table 2).

Association of TP53/TSG combinations with tumor relapse and metastasis

Among the 618 patients, 45 experienced recurrence. Although no significant differences were found in the proportions of local and distant relapses between the TP53+/TSG+, TP53+/TSG−, and TP53− groups (P=0.89) (Table S3). In terms of distant metastasis, although no significant differences were observed in the patterns of distant metastasis across most organs, patients with TP53+/TSG+ status were more likely to develop bone metastases than those with TP53+/TSG− or TP53− status (62.5% vs. 27.3% vs. 38.5%, P=0.34). Additionally, the overall comparison among TP53+/TSG+, TP53+/TSG−, and TP53− groups revealed a significant difference in brain metastasis incidence (P=0.03). Specifically, patients with TP53+/TSG− status were more prone to developing brain metastasis compared to those with TP53− status.

Significant correlation between TP53+/TSG+ and adverse prognosis

We found that patients with TP53+/TSG+ tumors had worse outcomes after surgery than those with TP53+/TSG− tumors (median RFS 14.7 vs. 25.6 months, P<0.001) or TP53− tumors (median RFS 14.7 vs. 30.5 months, P<0.001) (Figure 2A). However, there was no significant difference in RFS between TP53+/TSG− and TP53− tumor patients (P=0.09). Notably, EGFR mutation status was not significantly associated with RFS in Kaplan-Meier analysis (Figure S1A). Univariate Cox analysis identified risk factors for poor RFS, including age >50 years, male, smoking history, lobectomy, postoperative adjuvant therapy, tumor maximum diameter >30 mm, and solid density (all P<0.05). In multivariate Cox regression analysis, after adjusting for other variables, subsolid tumor density was a significant protective factor for RFS (HR =0.15, 95% CI: 0.07–0.32, P<0.001), while age >50 years was a risk factor (HR =3.2, 95% CI: 1.2–8.3, P=0.02). Patients with TP53+/TSG+ LUAD had worse prognosis compared to TP53+/TSG− patients (HR =3, 95% CI: 1.2–7.6, P=0.02) or TP53− patients (HR =3, 95% CI: 1.2–7.2, P=0.01) (Table 3). Additionally, risk curves stratified by TP53/TSG status showed that the baseline risk level of TP53+/TSG+ was higher within five years postoperatively than in the TP53+/TSG− and TP53− groups, with a sharp peak emerging in the fourth year after surgery (Figure 2B).

Figure 2 RFS and hazard risk by TP53/TSG status in stage I lung adenocarcinoma patients. (A) RFS curves for stage I lung adenocarcinoma patients by TP53/TSG status; (B) smoothed hazard estimates for stage I lung adenocarcinoma patients by TP53/TSG status. RFS, recurrence-free survival; TSG, tumor suppressor gene.

Prognostic stability of TP53/TSG status in the MSK cohort

In the MSK cohort, the proportion of patients with a smoking history was significantly higher in the TP53+/TSG+ group than in the other two groups (all P<0.05), and the overall tumor mutation burden (TMB) and nonsynonymous mutation burden were higher in the TP53+/TSG+ group compared to the TP53+/TSG− and TP53− groups (all P<0.05) (Table S4). Interestingly, the proportion of TP53+/TSG− patients with co-existing EGFR mutations was highest, followed by TP53− patients, with the lowest in the TP53+/TSG+ group (52.6% vs. 30.3% vs. 14.5%, all P<0.05). As in our cohort, EGFR mutation status had no significant impact on RFS (Figure S1B). During the follow-up, 11/62 (17.7%) of TP53+/TSG+ patients experienced recurrence, with shorter RFS compared to TP53+/TSG− (11.2 vs. 19.9 months, P=0.02) and TP53− (11.2 vs. 14.9 months, P=0.01). Kaplan-Meier curves showed that TP53+/TSG+ patients had significantly worse five-year prognosis compared to the other two groups (all P<0.05), and the RFS between the TP53+/TSG− and TP53− groups showed no difference, consistent with our cohort (P>0.99) (Figure 3A). The risk curves for the TP53+/TSG+ group showed small peaks at one and two to three years postoperatively, with a more pronounced peak beginning in the third year. In contrast, the TP53+/TSG− and TP53− groups displayed relatively flat risk curves (Figure 3B).

Figure 3 Validation in MSK cohort: RFS and hazard estimates by TP53/TSG status. (A) RFS curves for stage I lung adenocarcinoma patients of MSK cohort by TP53/TSG status; (B) smoothed hazard estimates for stage I lung adenocarcinoma patients of MSK cohort by TP53/TSG status. MSK, Memorial Sloan Kettering; RFS, recurrence-free survival; TSG, tumor suppressor gene.

Discussion

Despite advancements in diagnosing and treating early-stage NSCLC, particularly LUAD, tumor recurrence after surgery and adjuvant treatment remains a challenge (19,20). This may be linked to tumor heterogeneity beyond individual patient differences, underscoring the need for stratification of patients based on molecular characteristics to identify high-risk populations and implement more aggressive follow-up strategies. In current clinical practice, postoperative management of stage I LUAD typically involves regular follow-up, with the role of neoadjuvant therapy being less clearly defined and evaluated. Additionally, although previous research has associated TP53 and other TSG mutations with poor prognosis, most studies focused on single-gene mutations and did not specifically address stage I LUAD patients undergoing surgery (12,21). We conducted a retrospective analysis of 618 patients with stage I LUAD who underwent surgical treatment, aiming to evaluate how combinations of TP53 and TSG mutations correlate with clinicopathologic features and influence recurrence, metastasis, and prognosis. Our findings suggest that TP53 mutations, when co-exist with other TSG mutations, are closely associated with poor prognosis, increased TMB levels, and significantly worse outcomes. These results indicate that TP53+/TSG+ patients may benefit from neoadjuvant therapy.

Significant differences in clinical characteristics were observed between TP53+ and TP53− patients, with TP53+ patients showing higher proportions of males and individuals with smoking histories (both P<0.001), consistent with previous study (22). The MSK cohort also found that TP53+ mutations were associated with smoking, with a significantly higher proportion in the TP53+/TSG+ group compared to the TP53+/TSG− and TP53− groups (96.8% vs. 77.9% vs. 74.8%, P<0.001). Additionally, a greater proportion of TP53+ patients received postoperative adjuvant therapy. Interestingly, TP53+/TSG− patients had the highest co-occurrence of EGFR mutations, accounting for 14.6% of the population. This suggests that in the presence of EGFR+, other TSGs are less likely to co-occur with TP53 mutation. The co-mutation rate of EGFR and TP53 in early-stage resected LUAD patients is approximately 9.6% (23). Moreover, TP53− tumors were more frequently subsolid and smaller, both of which are associated with better prognosis (3,24). In contrast, TP53+/TSG+ tumors exhibited more aggressive features (spiculation, pleural indentation and VPI), further explaining the poor prognosis in these patients (25).

Relapse occurred in 7.3% of patients, which is lower than previously reported recurrence rates of 10–30% (4,5,26). This may be due to our cohort’s higher proportion of subsolid nodules ≤30 mm in size. While the overall relapse sites did not differ significantly between TP53+/TSG+, TP53+/TSG−, and TP53− patients, specific patterns of metastasis were observed. Specifically, TP53+/TSG+ patients showed a higher tendency for bone metastasis, while TP53+/TSG− patients were more likely to develop brain metastasis. Previous studies have shown that 66.7% (10/15) of LUAD patients with brain metastasis had TP53 mutations (27). TP53 and TSG mutations, including CDKN2A and PTEN, are common in LUAD bone metastases, with higher mutation levels in metastases than in primary tumors (28,29). This suggests that TP53 mutations and TSG status may influence disease progression by regulating tumor cell invasiveness and organ-specific metastatic potential.

Prognosis analysis revealed that TP53+/TSG+ patients had significantly shorter RFS compared to TP53+/TSG− and TP53− patients (14.7 vs. 25.6 vs. 30.5 months), with a marked recurrence peak in the fourth year postoperatively. This pattern aligns with findings from the MSK cohort, which showed a significant recurrence peak in the third year. These data highlight the need for close monitoring of TP53+/TSG+ patients, especially between the third and fourth postoperative years. Univariate and multivariate Cox regression analyses further confirmed TP53+/TSG+ status as an independent risk factor for recurrence (TP53+/TSG+ vs. TP53+/TSG− HR =3, 95% CI: 1.2–7.6, P=0.02; TP53+/TSG+ vs. TP53− HR =3, 95% CI: 1.2–7.2, P=0.01). Additionally, subsolid tumor density emerged as a protective factor (HR=0.15, CI: 95% CI: 0.07–0.32, P<0.001), which may be related to the slower growth rate and lower invasiveness of these tumors (30). Although the administration of postoperative adjuvant therapy was not associated with prognosis in stage I LUAD patients (HR =2.1, 95% CI: 1–4.3, P=0.051), the significantly higher TMB levels in TP53+/TSG+ patients suggest that they might benefit more from immunotherapy (31). According to the National Comprehensive Cancer Network guidelines, nivolumab combined with chemotherapy is recommended as neoadjuvant therapy for resectable NSCLC patients (tumor ≥4 cm or lymph node positive) (32). Although major pathological responses in early-stage lung cancer patients receiving preoperative nivolumab therapy are highly correlated with increased TMB (33), current guidelines do not recommend neoadjuvant for stage I LUAD patients. Certain oncogenic drivers (e.g., EGFR mutation, ALK rearrangement) are linked to reduced benefit from PD-1/PD-L1 inhibitors (34,35). Our study also indicates that TP53+/TSG+ patients are less likely to co-exist with EGFR mutations. These findings suggest that TP53+/TSG+ patients may represent a high-risk subgroup warranting further investigation in prospective studies to evaluate the potential benefit of neoadjuvant strategies.

Recent studies have advanced molecular risk stratification in stage I LUAD. Ho et al. identified a mutation load index (maxVAF) and microRNA signatures predictive of recurrence across substages (36), while another study demonstrated that EGFR mutation significantly reduces RFS, particularly when co-occurring with TP53 mutations (37). In both our own cohort and the MSK validation dataset, EGFR mutation status was not significantly correlated with RFS in Kaplan-Meier analysis (Figure S1). The discrepancy may reflect differences in patient composition, such as histologic subtypes, the prevalence of part-solid nodules, or the molecular background of the study populations.

This study has several limitations. As a single-center retrospective analysis with a cohort primarily consisting of ground-glass nodules and a high frequency of EGFR mutations, the generally favorable prognosis may limit generalizability. Additionally, the relatively smaller number of TP53+/TSG+ cases compared to TP53+/TSG− and TP53− patients mya weaken the statistical power of the Cox model. Furthermore, our genomic profiling panel does not include several important TSGs frequently mutated in LUAD, such as ARID1A, KEAP1, and RB1 (38-40), which are known to play critical roles in tumor progression and therapy resistance. The absence of these genes may underestimate TSG co-mutations and affect TP53+/TSG+ classification. To address this, we performed a supplemental analysis using the MSK dataset, which includes these TSGs (see Figure S2). The results confirmed the adverse prognosis of the TP53+/TSG+ subgroup, even with ARID1A, KEAP1, and RB1 included. In addition, standardized assessment of key histologic prognostic features—particularly micropapillary components and spread through air spaces (STAS)—was unavailable due to the study period [2016–2019], during which routine evaluation of micropapillary patterns (formally recognized in the 2015 World Health Organization classification) and STAS (first described in 2015) had not yet been widely adopted in pathology reporting (41,42).

Conclusions

Our study confirms the association between the co-existence of TP53 mutations with other TSG mutations and poor prognosis in LUAD. These findings provide new insights for patient stratification and suggest that more personalized treatment and follow-up plans should be considered for high-risk TP53+/TSG+ patients. Future research should assess whether intensified perioperative treatment, including neoadjuvant approaches, could improve outcomes in this genetically defined high-risk subgroup.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-29/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-29/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-29/prf

Funding: This study was supported by National Natural Science Foundation of China (CN) (No. 82370100), and National Science and Technology Innovation 2030 Major Project for Prevention and Treatment of Cancer, Cardiovascular, Respiratory and Metabolic Diseases (Nos. 2023ZD0506100, and 2023ZD0506106).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-29/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of West China Hospital of Sichuan University [approval No. 2024(2413)], with a waiver for written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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