Gastric cancer is one of the most common cancers worldwide, with a bad prognosis associated with late-stage diagnosis, significantly decreasing the overall survival. This highlights the importance of early detection to improve the clinical course of these patients. Although screening programs, based on endoscopic or radiologic approaches, have been useful in countries with high incidence, they are not cost-effective in low-incidence populations as a massive screening strategy. Additionally, current biomarkers used in daily routine are not specific and sensitive enough, and most of them are obtained invasively. Thus, it is imperative to discover new noninvasive biomarkers able to diagnose early-stage gastric cancer. In this context, liquid biopsy is a promising strategy. In this review, we briefly discuss some of the potential biomarkers for gastric cancer screening and diagnosis identified in blood, saliva, urine, stool, and gastric juice.

Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.

Gastric cancer (GC) is a major public health problem worldwide, with high mortality rates due to late diagnosis and limited treatment options. Biomarker research is essential to improve the early detection of GC. Technological advances and research methodologies have improved diagnostic tools, identifying several potential biomarkers for GC, including microRNA, DNA methylation markers, and protein-based biomarkers. Although most studies have focused on identifying biomarkers in biofluids, the low specificity of these markers has limited their use in clinical practice. This is because many cancers share similar alterations and biomarkers, so obtaining them from the site of disease origin could yield more specific results. As a result, recent research efforts have shifted towards exploring gastric juice (GJ) as an alternative source for biomarker identification. Since GJ is a waste product during a gastroscopic examination, it could provide a “liquid biopsy” enriched with disease-specific biomarkers generated directly at the damaged site. Furthermore, as it contains secretions from the stomach lining, it could reflect changes associated with the developmental stage of GC. This narrative review describes some potential biomarkers for gastric cancer screening identified in gastric juice.

The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis ≤60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer <40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9–67); p = 0.007 and OR:17.4 (95% IC 2.5–119.9); p = 0.004; respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.

Three percent of patients with pancreatic ductal adenocarcinoma (PDAC) present a germline pathogenic variant (GPV) associated with an increased risk of this tumor, CDKN2A being one of the genes associated with the highest risk. There is no clear consensus on the recommendations for surveillance in CDKN2A GPV carriers, although the latest guidelines from the International Cancer of the Pancreas Screening Consortium recommend annual endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI) regardless of family history. Our aim is to describe the findings of the PDAC surveillance program in a cohort of healthy CDKN2A GPV heterozygotes. This is an observational analysis of prospectively collected data from all CDKN2A carriers who underwent screening for PDAC at the high-risk digestive cancer clinic of the “Hospital Clínic de Barcelona” between 2013 and 2021. A total of 78 subjects were included. EUS or MRI was performed annually with a median follow-up of 66 months. Up to 17 pancreatic findings were described in 16 (20.5%) individuals under surveillance, although most of them were benign. No significant precursor lesions were identified, but an early PDAC was detected and treated. While better preventive strategies are developed, we believe that annual surveillance with EUS and/or MRI in CDKN2A GPV heterozygotes may be beneficial.