Gastric cancer, also known as stomach cancer, is the development of cancerous cells in the lining of the stomach. It is the third most frequent cause of cancer-related death globally (7,82,685 deaths per year) and the fifth most commonly diagnosed cancer (10,33,701 new cases in 2018). Thus, gastric cancer continues to be a challenge for the oncology domain. A substantial understanding of the molecular mechanisms underlying gastric carcinogenesis might lead to the identification of novel biomarkers for the early diagnosis, prognosis, and monitoring therapy response in gastric cancer patients [1].
Why do we need a new biomarker?
Although the incidence of gastric cancer has decreased over the past few decades, the 5-year survival rate is still low, largely because most patients are asymptomatic until the disease has reached an advanced stage. Additionally, the majority of cases of gastric cancer are diagnosed at an advanced stage, when the prognosis is poor, and the available treatments are not beneficial due to the disease progression. Gastric cancer diagnosis and prognosis currently rely only on invasive procedures like upper digestive endoscopy due to the limited sensitivity and specificity of the circulating biomarkers.
In the case of gastric cancer, there is a great demand for less invasive or non-invasive testing as well as extremely specific biomarkers. Liquid biopsies are currently employed for gastric cancer screening as it is moderately non-invasive as compared to the present gold standard of endoscopy. Various biomarkers can be detected which may be proteins, such as circulating tumor DNA, different kinds of RNA, exosomes, or other compounds linked to the carcinogenesis of gastric cancer [1,2].
A series of biological processes are involved in the development of tumors and cancer progression. Cells undergoing apoptosis or necrosis, exosomes, and other entities may all release cell-free DNA (cfDNA) into the bloodstream during these intricate events. The cfDNA formed from the tumors also known as circulating tumor DNA (ctDNA), comprises various tumor gene fragments that represent certain genetic modifications, such as methylation or mutation [3].
Circulating tumor DNA (ctDNA) can be extracted from liquid biopsies and it can serve as a biomarker for the diagnosis and monitoring of gastric cancer. ctDNA can be produced from the primary tumor cells, circulating tumor cells, or distant metastasis (spread of cancer to distant parts of the body). It can provide a comprehensive cross-section of the disease by providing details on methylation status, and genetic abnormalities such as mutations, amplifications, rearrangements, and copy number variation. ctDNA may provide a profound understanding of the:
Cancer heterogeneity.
Early biomarker recognition.
Therapeutic target recognition.
Real-time assessment of response to therapy.
Potential resistance.
Prognosis.
Previous evidence demonstrated the correlation of ctDNA levels with vascular invasion, 5-year survival rate, and peritoneal recurrence in gastric cancer. Additionally, previous research showed a substantial correlation of ctDNA levels with TNM (tumor, node, and metastasis) staging, tumor depth, lymph node metastasis, and distant metastasis with a specificity of 95% and a sensitivity of 62%. However, it has not yet proven to be useful in clinical practice because of the sophisticated technology required to detect ctDNA in the plasma [1,2].
How to detect circulating tumor DNA?
The appropriate analysis of ctDNA demands extremely sensitive and reliable analytical techniques due to its limited availability. ctDNA already demonstrated their utility in individualized treatment plans in gastric cancer patients which can be analyzed by:
Multiplex mass spectrometric SNP genotyping technology.
Real-time quantitative PCR (qRT-PCR).
Digital droplet PCR (ddPCR) with improved nucleic acid quantification.
Next-generation sequencing (NGS).
The FoundationACT an analytically validated and accurate blood-based assay for ctDNA by Foundation Medicine received breakthrough device designation by the FDA. In the future, this assay may end up being the first FDA-approved liquid biopsy assay to include multiple companion diagnostics and biomarkers [1,4].
What’s next?
Further investigations are required to optimize laboratory techniques for ctDNA extraction, quantification, and evaluation procedures to increase the sensitivity and broaden the use of ctDNA in the early detection and monitoring of gastric cancer.
References
1. Necula, L. et al. 'Recent advances in gastric cancer early diagnosis'. World J Gastroenterol. (2019) 25(17), 2029–2044. DOI: 10.3748/wjg.v25.i17.2029.
2. Haque, E. et al. 'Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer'. Cancers (Basel). (2022) 14(22), 5615. DOI: 10.3390/cancers14225615.
3. Gao, Y. et al. 'Diagnostic and prognostic value of circulating tumor DNA in gastric cancer: a meta-analysis'. Oncotarget. (2016) 8(4), 6330–6340. DOI: 10.18632/oncotarget.14064.
4. 'Foundation Medicine Announces Commercial Launch of Liquid Biopsy Assay, FoundationACTTM | Foundation Medicine' [https://www.foundationmedicine.com/press-releases/07936a8f-b1e6-4fb5-a4a8-26c909f684c5].
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