# Genetic risk stratification and preventive strategies for double primary HNSCC and ESCC: a single-center cohort study

## TL;DR

This study explores risk factors and genetic influences for patients with two primary cancers of the head and neck and esophagus, emphasizing the role of smoking and alcohol.

## Contribution

The study identifies specific risk factors and genetic markers linked to double primary cancers of HNSCC and ESCC.

## Key findings

- Smoking was more common in patients with early ESCC and advanced HNSCC.
- Advanced cancer stage, smoking, and low BMI were identified as poor prognostic factors.
- Inactive ALDH2 and CYP2A6 genotypes were associated with drinking and smoking behaviors.

## Abstract

Head and neck squamous cell carcinoma (HNSCC) and esophageal SCC (ESCC) share risk factors, such as alcohol consumption, smoking, and aldehyde dehydrogenase 2 (ALDH2) gene polymorphisms. However, the involvement of these factors in the occurrence of double primary cancers remains unclear. This study aimed to examine the risk factors for double cancers.

This single-center study analyzed 113 patients with HNSCC and ESCC diagnosed between 2014 and 2022, classified into four stage-based groups: Group A (early ESCC + early HNSCC), Group B (early ESCC + advanced HNSCC), Group C (advanced ESCC + early HNSCC), and Group D (advanced ESCC + advanced HNSCC). Associations among clinical factors, Lugol-voiding lesions (LVLs), and prognosis were evaluated. Genetic analyses of ALDH2, CYP2A6, and ADH1B were performed in 20 patients, and multivariate Cox analysis included tumor stage, smoking, and body mass index (BMI).

Smoking was more common in Group B than in Group A (89.0% vs. 73.5%, p = 0.013) and was associated with Lugol-voiding lesions (p = 0.027). Three-year overall survival declined with advancing stage (93.3%, 74.0%, 33.3%, and 36.4% for Groups A–D; p < 0.001). Multivariate analysis identified advanced stage, smoking (HR = 1.9, p = 0.009), and low BMI (< 18.5 kg/m2, HR = 2.3, p = 0.024) as poor prognostic factors. Inactive ALDH2 correlated with drinking history, and poorly metabolizing CYP2A6 was less frequent among smokers.

Heavy smoking was associated with the development of LVLs and poor prognosis in those with double primary cancers. ALDH2 and CYP2A6 may contribute to cancer risk, underscoring the importance of abstinence from alcohol and smoking in preventive healthcare.

The online version contains supplementary material available at 10.1007/s10388-026-01187-2.