Introduction

Stomach cancer, also known as gastric cancer (GC), is a multistep and multifactorial malignancy determined by the complex interaction between genetic and environmental factors.¹ Its high aggressiveness and heterogeneity still represent a worldwide concern in public health², as it is the fifth most common cancer, and the fourth leading cause of death in the globe. Because of its rapid progression to an advanced stage, patients diagnosed with GC, on average, survive for less than 1 year after diagnosis.³

On a topographic level, stomach cancer can be classified into two types: 

• cardia stomach cancer
• non-cardia stomach cancer

The most common type of all stomach cancers, approximately 90%, includes adenocarcinomas, categorised into two subtypes, such as diffuse and intestinal cancers.⁴ They differ respectively in morphology, clinical symptoms, genetics, age and gender distribution, being decisive for surgical treatment, particularly in determining the extent of stomach resection.²

The primary risk factors causing GC include modifiable and non-modifiable risk factors, depending on whether they can be changed through lifestyle or medical interventions.^1-3-4

Non-modifiable risk factors

 Factors, defined as non-modifiablecannot be changed in order to prevent the occurrence and development of stomach cancer. They include intrinsic components such as age, gender, genetic predispositions, and ethnicity.⁵

Age

Age plays a crucial role in the development of stomach cancer, with GC being more common in individuals over the age of 50. It is well known that many mechanisms of human health are closely linked to ageing, such as the accumulation of cellular changes, like DNA damage, which contribute to the increased risk of developing various types of cancer. In addition, as the body ages, the immune system becomes weaker, a process known as immunosenescence. As a result, in cases of gastric cell transformations, the body’s ability to detect and get rid of tumour cells is slightly reduced. Moreover, the gastric mucosa is another component that gradually loses its capacity for self-repair with age, increasing the likelihood of chronic inflammation and the potential onset of stomach cancer.⁶

Gender

Stomach cancer occurs more in men than in women. Several studies have shown that this incidence is worldwide and possibly related to both biological and lifestyle aspects. In fact, men tend to smoke and consume alcohol more than women, as these behaviours are highly associated with cancer risk. Additionally, it’s been shown that males are more likely to have Helicobacter pylori infections, known to be a crucial cause of GC.⁶

Regarding overall survival between males and females, studies have shown that women present a better prognosis, especially in the first stage of the disease and in advanced age, compared to men. Probably it is due to the protective effect of estrogen, the female sex hormone, which appears to reduce inflammation, regulate immune response, and potentially suppress H. pylori growth.^6,7 Otherwise, in younger patients (<59 years) with GC, gender-related differences in survival are minimal. This might be due to the fact that younger women may not benefit from the positive effects of estrogens yet.⁷

Family history

Almost 90% of all GCs occur casually. While only 10 to 20% of cases have a positive family history (FH), with a higher risk of GCs by up to 85% if the affected relative is a sibling or a parent. The familial factor depends on a combination of genetic and environmental influences shared within the family. Only a few cases of FH are due to inherited genetic syndromes, such as Hereditary Diffuse Gastric Cancer (HDGC), linked to CDH1 mutations; most cases are attributed to shared environmental factors.^6,8

 Moreover, the risk is higher for non-cardia GC than for cardia GC, probably due to the familial transmission of H. pylori infection, whereas cardia GC is more strongly associated with obesity, gastroesophageal reflux, and smoking.⁸

Ethnicity

Gastric cancer is not equally distributed across the globe, as it is closely linked to genetic and environmental influences. In fact, the highest prevalence is seen in Asia, Eastern Europe, and Latin America. Factors such as socioeconomic status, H. pylori infection, diet, and lifestyle contribute to these disparities. Moreover, even the quality of water, air, and soil can play a role in increasing the risk, especially in places where high-salt diets and low intake of fruits and vegetables are commonly consumed.⁶

Modifiable risk factors

These modifiable factors can be significantly changed in order to reduce the risk of the onset of GC. The main ones include lifestyle choices such as dietary habits, smoking, and drinking alcohol, H. pylori infection and others.⁶

Helicobacter pylori Infection

Helicobacter pylori is a bacterium crucial for causing stomach cancer, as it has been recognised as Group 1 carcinogen. In fact almost 90% of non-cardia gastric cancers are induced by H. pylori.⁶ H. pylori infection is commonly asymptomatic in most people, but it can develop in gastritis and rapidly progress to serious malignancies. When H. pylori infects the stomach, chronic inflammation followed by the release of dangerous toxins, such as CagA e VacA can occur.

These toxins are very difficult to get rid of due to damage that has occurred to the DNA of the host’s cells in the gastric area. In this way, infected cells are no longer able to repair their damaged DNA, resulting in potential intestinal metaplasia, dysplasia, and finall,y gastric cancer.⁹ Given the serious impact of H. pylori, it is fundamental to undergo early treatment with antibiotic therapies, especially before precancerous changes, as it can significantly reduce cancer risk⁶ by about 46% in healthy people, and by 55% in people with a family history background.¹⁰

Dietary factors

It is well-known that high salt intake contributes to the onset of GC, due to the damage to the gastric mucosa. Salt-preserved foods, salted fish, daily consumption of salted tea in Mongolia, as well as noodles and dumplings in Korea–that are rich in sodium, are strong risk factors. Consumption of processed and red meat is also a significant risk factor that increases the likelihood by 11% to 51%. This is due to the formation of carcinogenic compounds, such as polycyclic aromatic hydrocarbons and heterocyclic aminess during the cooking at high temperatures.

Moreover, fried foods and foods high in saturated fats can also lead to the formation of carcinogenic compounds and to obesity, insulin resistance, and chronic inflammation, which are risk factors for GC. Fast food consumption is also known to be risky because of the high concentration of fats, high sodium, and carcinogens. Conversely, fruits and vegetables contain nutrients like vitamin C, carotenoids, vitamin E, and phenolic compounds that are associated with reduced GC risk.⁶

Smoking

Smoking is crucial in determining GC, as well as other types of cancer, being classified as a Group 1 carcinogen. Its harmful effects are mainly attributed to over 5000 chemicals contained in tobacco cigarettes and waterpipe, 98 of which have been identified as cancer-causing. However, some studies also demonstrated how smoking before meals, combined with genetic predisposition factors, contributes to increasing the risk, particularly in specific populations. Statistically, current smokers have a 53% higher risk of GC compared to never smokers, while former smokers have a 30% risk, highlighting how quitting smoking can substantially reduce this risk over time, especially after 10-15 years.⁶

Alcohol consumption

Heavy alcohol consumption is linked to an increased risk of GC, confirmed by several studies around the world. In particular, a prolonged alcohol intake appears to cause non-cardia gastric cancer, especially in men. Moreover, a combination of recurrent alcohol use, red meat consumption, and H. pylori infection further raises the cancer risk.⁶

Obesity

Obesity can also be a determinant of stomach cancer, particularly in the cardia subtype. Obesity as a GC factor, with a BMI ≥30, appears to be risky in men and postmenopausal women. This is mainly due to a chronic inflammation promoted by obesity, where a consistent production of cytokines and a state of insulin resistance may damage DNA and support cancer growth. Thus, intentional weight loss followed by healthy weight maintenance can be fundamental in obese individuals to reduce the risk of GC.⁶

Medical conditions 

Chronic gastritis

Chronic gastritis is a long-term inflammatory condition considered a high-risk factor for GC, especially when there is progressive pathological transformation in the gastric mucosa. This condition can cause atrophic gastritis and intestinal metaplasia, which may potentially progress to dysplasia and neoplastic transformation, thus increasing GC risk. Moreover, this risk is even higher if chronic gastritis is associated with H. pylori infection.¹¹

Pernicious anaemia

A possible reason for the increasing GC risk may be the increasing prevalence of autoimmune conditions, which are known to cause inflammation, which is involved in the initiation of many cancers.

GC has been strongly linked to pernicious anaemia, which results from advanced autoimmune gastritis, caused by the gradual destruction of gastric parietal cells. This leads to a decreased intrinsic factor production and to a reduced ability to absorb vitamin B12.

This atrophic gastritis results in chronic inflammation that increases the risk of cancer. Furthermore, pernicious anaemia has been associated with non-cardia cancer.¹²

Previous stomach surgery

Gastric surgeries, including partial gastrectomy or gastric bypass, have been identified as risk factors in GC. Probably due to the fact that they can drastically alter stomach structure and function, affecting components like acid secretion, bile reflux, and microbiota composition.⁶

Epstein-Barr virus (EBV) infection

GC induced by Epstein-Barr virus (EBV) infection is rare and has unique molecular features. This virus can drive changes in DNA that contribute to cancer development. Although EBV-induced stomach cancer shows different symptoms, such as the presence of lymphatic tissue around the tumour, it is less likely to spread to the lymph nodes and has a better prognosis.¹³

Summary

Stomach cancer is a very complex disease caused by a combination of genetic, environmental, infectious, and behavioural factors. While some factors, such as age, gender, and family predisposition, cannot be modified, many others can be changed by simply adopting healthier lifestyle behaviours. In a few words: 

• H. pylori infection is one of the main risk factors, although it is curable
• Healthy diets rich in fruits and vegetables, with a low intake of salty foods, are a key protective factor
• Reducing smoking and alcohol abuse significantly decreases the risk
• Paying attention to persistent symptoms, such as reflux, sudden weight loss, anaemia, etc., is crucial in order to prevent serious consequences, including the development of stomach cancer