Gallbladder cancer occurs when there is an overgrowth of cells in the lining of the gallbladder. It ranks sixth among gastrointestinal malignancies and is the most common cause of cancer-related death among biliary tract cancers. Therefore, gallbladder cancer still poses a problem for the field of oncology. A deeper comprehension of the molecular pathways behind gallbladder carcinogenesis may make it possible to find new biomarkers for the early diagnosis of gallbladder cancer.
What is the need for a new biomarker?
The majority of patients with this cancer are asymptomatic until the disease has progressed to an advanced stage. This is the reason for the low five-year survival rate, even though the incidence of gallbladder cancer has reduced over the past few decades. Gallbladder cancer is typically discovered at an advanced stage, when the prognosis is guarded, and the existing treatments are ineffective. Due to the low sensitivity and specificity of circulating biomarkers for these cancers, the diagnosis and prognosis of gallbladder cancer presently rely on invasive techniques like upper endoscopy and endoscopic retrograde cholangiopancreatography exclusively.
In the case of gallbladder 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 gallbladder cancer screening as they are moderately non-invasive compared to the present gold standard of endoscopy. These blood tests can find biomarkers, which can be proteins, circulating tumor DNA, different types of RNAs, exosomes, or other compounds linked to the carcinogenesis of gallbladder cancer [1].
What is circulating tumor DNA?
The formation of tumors and the development of cancer are influenced by numerous biological mechanisms. Cell-free DNA (cfDNA) may be released into the circulation during these complex processes by the cells that are undergoing apoptosis, necrosis, and other entities. The circulating tumor DNA (ctDNA) is the cell-free DNA that is generated from the tumors. It is made up of multiple tumor gene segments that represent different genetic alterations, such as methylation or mutation [2].
It is possible to extract circulating tumor DNA (ctDNA) from liquid biopsies, and this DNA can be used as a biomarker for the detection and monitoring of gallbladder cancer. Primary tumor cells, circulating tumor cells, and distant metastases can all produce this ctDNA. By providing information on methylation status and genetic abnormalities such as mutations, amplifications, rearrangements, and copy number variations, it can give a thorough information of the disease. The following aspects of gallbladder cancer may be profoundly understood with the help of ctDNA:
Heterogeneity in gallbladder cancer.
Early detection of biomarkers.
Real-time evaluation of the therapy response.
Identification of the therapeutic targets.
Prognosis of gallbladder cancer [3].
How to detect circulating tumor DNa?
Due to the restricted availability of ctDNA, accurate analysis requires exceptionally sensitive and trustworthy analytical procedures. The following are the procedures to explore ctDNA in gallbladder cancer:
Multiplex mass spectrometric SNP genotyping technology
Real-time quantitative PCR
Digital droplet PCR with improved nucleic acid quantification.
Next-generation sequencing (NGS) [4].
What is the future of ctDNA in GBC?
The link between ctDNA levels and vascular invasion, 5-year survival rate, and recurrence in gallbladder cancer has already been well established in the literature. Furthermore, earlier studies demonstrated a strong association between ctDNA levels and TNM (tumor, node and metastasis) staging, tumor depth, lymph node metastasis, and distant metastasis. Due to the advanced technology required to identify ctDNA in the plasma, it has not yet proven to be very beneficial in the determination of gallbladder cancer [5].
Bottom line!
To improve the sensitivity and to expand the use of ctDNA in the early identification and monitoring of gallbladder cancer, more research is needed to optimize laboratory methodologies for ctDNA extraction, quantification, and evaluation procedures.
References
1. J.-Y. Han et al., “Liquid Biopsy from Bile-Circulating Tumor DNA in Patients with Biliary Tract Cancer,”Cancers (Basel), vol. 13, no. 18, p. 4581, Sep. 2021, doi: 10.3390/cancers13184581.
2. A. RIZZO, A. D. RICCI, S. TAVOLARI, and G. BRANDI, “Circulating Tumor DNA in Biliary Tract Cancer: Current Evidence and Future Perspectives,”Cancer Genomics Proteomics, vol. 17, no. 5, pp. 441–452, Sep. 2020, doi: 10.21873/cgp.20203.
3. K. Mody et al., “Circulating Tumor DNA Profiling of Advanced Biliary Tract Cancers,”JCO Precision Oncology, no. 3, pp. 1–9, Dec. 2019, doi: 10.1200/PO.18.00324.
4. “ctDNA May Predict Worse Metastatic Biliary Tract Cancer Prognosis.” https://www.medscape.com/viewarticle/965203 (accessed May 29, 2023).
5. “Promise of bile circulating tumor DNA in biliary tract cancers - Kearney - 2023 - Cancer - Wiley Online Library.” https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34715?af=R (accessed May 28, 2023).
Comments