# Familial Non-Hereditary Gastric Cancer: Diagnosis, Management, Molecular Characteristics and Future Perspective

## TL;DR

This paper reviews what is known about gastric cancer in families without inherited genetic mutations, aiming to improve diagnosis and treatment for these families.

## Contribution

The paper provides a comprehensive review of the multifactorial causes and management of familial non-hereditary gastric cancer.

## Key findings

- Familial non-hereditary gastric cancer is likely caused by a combination of H. pylori infection, genetic polymorphisms, and shared environmental factors.
- Molecular features include microsatellite instability, CDH1 promoter hypermethylation, and mutations in TP53, RHOA, and DNA repair genes.
- Current management includes H. pylori eradication, genetic testing, and endoscopic surveillance.

## Abstract

Gastric cancer is one of the most common and deadly cancers worldwide. While some families carry genetic germline mutations that clearly increase their risk, there are also families with several members affected by stomach cancer but without any known inherited genetic cause. These cases are called familial non-hereditary gastric cancer. This condition is still poorly understood, and there is little guidance on how to identify, follow up, or treat people at risk. Our review aims to describe what is currently known about this gastric cancer risk condition, including possible risk factors, and clinical and molecular features. By gathering and analyzing the available evidence, we hope to help doctors recognize this condition earlier and guide future research. Ultimately, improving our understanding could lead to better prevention, monitoring and treatment strategies for families affected by this form of gastric cancer.

Background/Objectives: Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. While most cases are sporadic, approximately 10% show familial clustering with only a minority explained by known hereditary syndromes. The remaining, termed familial non-hereditary gastric cancer (FNHGC), lack a defined high-penetrance germline mutation. This review aims to summarize current knowledge regarding the diagnosis, risk factors, molecular characteristics and management of FNHGC. Methods: A comprehensive narrative review of the literature was conducted focusing on epidemiologic, molecular and clinical studies addressing families with multiple GC cases but no identified germline mutation. Results: The etiology of FNHGC is multifactorial, and H. pylori, with its related chronic gastritis, is probably the key driver. Familial clustering likely occurs when combined with other elements such as genetic polymorphisms, shared exposures to risk factors or even epigenetic phenomena. Molecular profiling reveals distinct patterns in familial tumors such as more frequent microsatellite instability; somatic CDH1 promoter hypermethylation; and recurrent somatic mutations in TP53, RHOA and DNA repair genes. Current management focuses on genetic testing to rule out hereditary syndromes, endoscopic surveillance and mitigation of risk factors, with eradication of H. pylori paramount. Conclusions: FNHGC represents a distinct subgroup of GC characterized by a multifactorial etiology related to exposure to risk factors and genetic susceptibility although significant gaps remain in fully explaining the condition. Ongoing research holds promise to provide tools for better detection and prevention in order to reduce the burden of GC in familial settings.