The pathogenic germline ETV4 P433L mutation identified in multiple primary lung cancer affect tumor stem-like property by Wnt/β-catenin pathway

Sep 21, 2026

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Multiple primary lung cancer (MPLC) shows rising incidence and complex genetic heterogeneity, while the underlying germline drivers remain incompletely defined. Whole genome sequencing and linkage analysis in a dominant familial lung disease cohort, followed by Sanger screening across additional MPLC patients, identified a deleterious heterozygous ETV4 P433L variant. Functional studies in A549 and H322 cells and models demonstrated altered migration and enhanced stem-like properties via Wnt/β-catenin pathway activation, supporting a tumor-promoting role.

LanguageEnglish

CategoryResearch & Report

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Pages13

Reading Time33 min

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Introduction

Multiple primary lung cancer definition and epidemiology

Genetic heterogeneity and known risk correlations

Study rationale and research gap

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN The pathogenic germline ETV4 P433L mutation identiﬁed in multiple primary lung cancer affect tumor stem-like property by Wnt/β-catenin pathway Yu Liu 1,6, Lingling Fang2,6, Yalong Wang2,6, Tao Fan3, Liyu Wang3, Chu Xiao3, Ziqin Deng3, Wenpeng Cai3, Bo Zheng4, Junfeng Qiu5, Chunxiang Li 3 ✉ and Jie He 3 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | The occurrence of multiple primary lung cancer (MPLC) has witnessed a signiﬁcant surge in recent years within the Chinese population. MPLC is distinguished by its potential genetic susceptibility and notable genetic heterogeneity. Investigating the etiology of MPLC holds substantial clinical importance.The whole genome sequencing (WGS) and genome-wide linkage analysis were performed in a family affected by a dominant form of lung abnormalities. Speciﬁcally, ﬁve family members were diagnosed with MPLC, while nine members had pulmonary nodules and one normal member. To conﬁrm the potential pathogenic germline mutations sites, Sanger sequencing was performed in an additional 162 MPLC family patients. Furthermore, molecular biology experiments were conducted to investigate the function and the mechanism of the identiﬁed pathogenic mutation site in lung cancer A549 and H322, both in vitro and in vivo. Linkage analysis revealed the presence of shared genomic regions among affected family members. Subsequent exome sequencing identiﬁed a deleterious variant within these linkage intervals, speciﬁcally a heterozygous mutation in ETS-oncogene transcription factors 4 (ETV4) . This particular variant was found in affected family members at a rate of 13 out of 15 individuals. Furthermore, ETV4 P433L mutation could be detected in an additional MPLC family patients and mutation frequency was 3.7%(6 out of 162) . The ETV4 P433L mutations site was introduced into lung cancer cell lines, resulting in altered migration and stem-like properties of the cancer cells. Further investigation revealed that the activation of the Wnt/β-catenin signaling pathway, which is associated with stemness, could be attributed to the presence of the ETV4 P433L mutation, suggesting its involvement in tumor promotion. A novel pathogenic germline mutation, ETV4 P433L, was identiﬁed in a dominant MPLC family, with a mutation rate of 3.7% among MPLC family patients. The ETV4 P433L mutation was found to impact the stem- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | like properties and migration of tumors through Wnt/β-catenin signaling pathway. | | | | | Cell Death and Disease (2024)15:738; [https://doi.org/10.1038/s41419-024-07129-z](https://doi.org/10.1038/s41419-024-07129-z) | | | | | | INTRODUCTION Multiple primary lung cancer (MPLC) is deﬁned as the simultaneous or sequential development of two or more primary lung cancers in the same patient [1] . Approximately 15% of lung cancer patients exhibit the development of two or more lesions [2], with MPLC being a frequently observed manifestation settings [3–5] . The prevalence of MPLC has exhibited a notable rise and is observed in approximately 0.2–8% of newly diagnosed lung carcinomas because of the utilization of low-dose computed tomography (LDCT) cases [6, 7] . MPLC, or multiple ground glass/ lepidic (GG/L) nodules, possesses distinctive genetic characteristics and warrants consideration as an independent disease different from lung cancer [8, 9] . The precise etiology of this disease remain unclear, although prior research has indicated a strong correlation between smoking [10–12], ﬁeld cancerization [13–15], and familial heredity [16] in the onset of MPLC. Our research team revealed a remarkably high incidence rate of 35.8%(220 out of 625) among ﬁrst-degree relatives [12] . The 162 cases MPLC were identiﬁed among these 220 family history patien

FAQs

What is multiple primary lung cancer (MPLC) in this study?

MPLC refers to the simultaneous or sequential development of two or more primary lung cancers in the same patient, a condition reported in a notable fraction of lung cancer cases.

How was the ETV4 P433L pathogenic germline mutation identified?

The study used whole genome sequencing and genome-wide linkage analysis in an affected family, then applied Sanger sequencing to confirm the mutation in additional MPLC patients, supported by exome sequencing within linkage intervals.

What effect does ETV4 P433L have on tumor cells and signaling?

Introducing ETV4 P433L into lung cancer cell lines altered migration and increased stem-like properties, linked to activation of the Wnt/β-catenin signaling pathway.

Sep 21, 2026

Uploaded by Rowan