Multi Omics Molecular Characteristics and Immunophenotyping of Lung Signet Ring Cell Carcinoma

This study aims to reveal the molecular characteristics and immune microenvironmental profile of signet ring cell carcinoma of the lung (LSRCC) in the Chinese population through integrated multi-omics analyses. The project plans to enroll formalin-fixed paraffin-embedded (FFPE) tissue samples and paired adjacent tissues from 39 patients with previously untreated LSRCC to establish a Chinese LSRCC molecular database. Whole-exome sequencing (WES) will be used to analyze gene mutations, such as single nucleotide variants (SNVs), copy number variants (CNVs), and fusion events. RNA-seq will be used to screen for differentially expressed genes (DEGs) and perform immunophenotyping, while multiplex immunohistochemistry will be employed to quantify the tumor immune microenvironment (TIME). The successful implementation of this project is expected to identify novel molecular biomarkers specific to the Chinese LSRCC population, enhance understanding of the unique immune phenotypes within this group, and-combined with clinical follow-up-establish correlations between molecular/immune signatures and therapeutic efficacy assessments, thereby providing evidence-based medical support for subsequent personalized precision diagnosis and treatment of LSRCC in this population.

Study Overview

• Status: Recruiting
• Conditions: Signet Ring Cell Carcinoma of the Lung
• Intervention / Treatment: Drug: Patients with specific TIME subtype and ALK fusion mutations (confirmed via RNA-seq and OncoKB annotation) will receive tyrosine kinase inhibitors (TKIs, e.g., alectinib or crizotinib) as first-line

Detailed Description

This study aims to reveal the molecular characteristics and immune microenvironmental profile of signet ring cell carcinoma of the lung (LSRCC) in the Chinese population through integrated multi-omics analyses. The project plans to enroll formalin-fixed paraffin-embedded (FFPE) tissue samples and paired adjacent tissues from 39 patients with previously untreated LSRCC to establish a Chinese LSRCC molecular database. Whole-exome sequencing (WES) will be used to analyze gene mutations, including single nucleotide variants (SNVs), copy number variants (CNVs), and fusion events. RNA-seq will be utilized to screen for differentially expressed genes (DEGs) and conduct immunophenotyping, while multiplex immunohistochemistry will be applied to quantify the tumor immune microenvironment (TIME). The successful implementation of this project is expected to identify novel molecular biomarkers specific to the Chinese LSRCC population, enhance understanding of the unique immune phenotypes within this group, and-combined with clinical follow-up-establish correlations between molecular/immune signatures and therapeutic efficacy assessments, thereby providing evidence-based medical support for subsequent personalized precision diagnosis and treatment of LSRCC in this population.

• Study Type: Observational
• Enrollment (Estimated): 39

Contacts and Locations

• Study Contact: Name: Shirong Zhang; Phone Number: +86-0571-56007664; Email: shirleyz4444@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310006
      • Recruiting
      • Centre of Translational Medicine, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine
      • Contact: Shirong Zhang; Phone Number: +86-0571-56007664; Email: shirleyz4444@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll adults (≥18 years) with newly diagnosed, histopathologically confirmed lung signet ring cell carcinoma (LSRCC) who have not received prior systemic anticancer therapy. All cases must have formalin-fixed paraffin-embedded (FFPE) tissue samples available. Additional inclusion criteria include measurable disease per RECIST v1.1 on contrast-enhanced CT, ECOG performance status 0-2, and adequate organ function. Patients with concurrent malignancies, prior exposure to any ALK-targeted agent, or known contraindications to TKI therapy are excluded.

Description

Inclusion Criteria:

1.Histologically confirmed, previously untreated LSRCC; 2. Adequate FFPE tumor tissue and paired adjacent non-tumor tissue available; 3. Expected survival ≥ 12 weeks; 4. Patients (or their legal guardians) willing and able to provide written informed consent; 5.Availability of complete pathology and imaging data.

Exclusion Criteria:

1. Prior systemic anticancer therapy; 2. Secondary LSRCC (i.e., metastatic signet ring cell carcinoma originating from a non-lung primary site); 3. Concurrent other malignancies; 4. Incomplete pathology results, missing imaging data, or unreliable follow-up information; 5. Pregnancy or lactation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Chinese LSRCC Multi-omics Cohort; This cohort comprises 39 treatment-naïve patients with histopathologically confirmed lung signet ring cell carcinoma (LSRCC) enrolled across multiple medical centers in China. Key molecular features include frequent mutations in core genes, distinct copy number variations (CNVs), and transcriptional up- and down-regulation of novel biomarkers. Tumor immune microenvironment (TIME) profiling classified patients into three subtypes: I, II, and III.

Drug: Patients with specific TIME subtype and ALK fusion mutations (confirmed via RNA-seq and OncoKB annotation) will receive tyrosine kinase inhibitors (TKIs, e.g., alectinib or crizotinib) as first-line; Patients with specific TIME subtype and ALK fusion mutations (confirmed via RNA-seq and OncoKB annotation) will receive tyrosine kinase inhibitors (TKIs, e.g., alectinib or crizotinib) as first-line therapy. Clinical response will be assessed via RECIST v1.1 criteria using serial CT imaging (baseline, 8 weeks, and every 12 weeks thereafter). Correlative analyses will evaluate TKI efficacy in relation to TIME subtype, ALK fusion variant, and multi-omic signatures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Week 8 Objective Response Rate (ORR) by RECIST v1.1 in ALK Fusion-Positive LSRCC Patients with Hybrid TIME Subtype	Objective Response Rate (ORR), defined as the proportion of patients achieving Complete Response (CR) or Partial Response (PR) per RECIST v1.1 criteria, assessed via contrast-enhanced CT at Week 8 following initiation of TKI therapy.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Time from initiation of TKI therapy to the first documented radiologic disease progression (as per RECIST v1.1) or death from any cause, whichever occurs first.	From baseline until disease progression or death (assessed up to 24 months).
Overall Survival (OS)	Time from initiation of TKI therapy to death from any cause.	From baseline until death from any cause (assessed up to 36 months).
Duration of Response (DoR)	Among patients who achieve an objective response (CR or PR), the time from the first documented response to disease progression or death from any cause.	From first response until progression or death (assessed up to 24 months).
Disease Control Rate (DCR) at Week 8	Proportion of patients achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST v1.1 at Week 8.	8 weeks
Safety and Tolerability of TKI Therapy	Incidence and severity of adverse events, laboratory abnormalities, and dose modifications, graded according to NCI-CTCAE version 5.0.	From initiation of TKI therapy until 30 days after the last dose (assessed up to 24 months).
Concordance Between Baseline mIHC-Defined TIME Subtypes and Treatment Outcomes	Agreement between baseline multiplex immunohistochemistry (mIHC)-defined TIME subtypes (I, II, III) and real-world treatment outcomes (ORR and PFS) across the full cohort.	From baseline until disease progression or death (assessed up to 24 months).

Collaborators and Investigators

• Sponsor: First People's Hospital of Hangzhou
• Collaborators: Zhejiang University; General Hospital of Ningxia Medical University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: September 19, 2025
• First Submitted That Met QC Criteria: September 28, 2025
• First Posted (Actual): October 3, 2025

Study Record Updates

• Last Update Posted (Actual): October 3, 2025
• Last Update Submitted That Met QC Criteria: September 28, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Multi-omics analysis; LSRCC; Immune subtyping
• Additional Relevant MeSH Terms: Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperidines; Aminopyridines; Crizotinib; alectinib
• Other Study ID Numbers: 2025ZN214-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes