Personalized treatment of perihilar cholangiocarcinoma based on tumor genetic and molecular characteristics

Abstract

This editorial discusses the article written by Tchilikidi et al that was published in the latest edition of the World Journal of Gastrointestinal Surgery. Genetic and molecular profiling of perihilar cholangiocarcinoma (pCCA) has identified a number of key abnormalities that drive tumor growth and spread, including pyruvate kinase M2, proline rich 11, and transcription factor 7, etc. pCCA has specific genetic and molecular features that can be used to develop personalized treatment plans. Personalized treatment approaches offer new opportunities for effectively targeting the underlying drivers of tumor growth and progression. The findings based on tumor genetic and molecular characteristics highlight the importance of developing personalized treatment strategies.

Key Words: Perihilar cholangiocarcinoma; Molecular characteristics; Tumor genetic; Personalized; Treatment

Core Tip: Genetic and molecular profiling of perihilar cholangiocarcinoma (pCCA) has identified a number of key abnormalities that drive tumor growth and spread. pCCA is still hard to treat, and individualized anticancer treatment is required, which is supposed to be according to the genetic and molecular features. The personalized treatment should be explored to improve outcomes for patients with this challenging disease.

INTRODUCTION

Cholangiocarcinoma accounts for about 15%-20% of all hepatobiliary tumors[1]. Globally, the average age at onset is 50 years[2]. According to the different origin and location of cholangiocarcinoma, it is divided into three subtypes: Intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma[3,4]. pCCA and distal cholangiocarcinoma were previously collectively referred to as extrahepatic cholangiocarcinoma, but with the progress of molecular biotechnology and the differences in treatment methods, it is currently believed that they are two subtypes of cholangiocarcinoma with different properties, which need to be differentiated in the process of research and treatment[5].

Among the three types of cholangiocarcinoma, pCCA is the most common, accounting for more than 60% of all cholangiocarcinoma[6,7]. Obesity, diabetes, and metabolic syndrome have recently been recognized as risk factors[8]. The risk factors associated with pCCA include advanced age, male sex, liver cirrhosis, inflammatory bowel disease, chronic pancreatitis, and liver obstructive diseases (such as biliary ascariasis, liver fluke disease, and hepatic schistosomiasis). The most closely related to pCCA is primary sclerosing cholangitis[9]. Recent advances in molecular pathobiology and therapeutic approaches delves into the multidisciplinary management of pCCA, emphasizing the role of recent research in molecular pathobiology to improve patient outcomes.

Morphologically, pCCA can be divided into three types: Papillary, nodular, and sclerotic. According to histological classification, pCCA can be divided into adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, undifferentiated carcinoma, carcinoid, sarcoma, etc. More than 90% of pCCA is adenocarcinoma. pCCA often invades blood vessels, lymphatic vessels, and hilar structures. pCCA also has a very important feature with nerve invasion, which is an independent prognostic factor for patients with pCCA[10].

Recent rapid progress in molecular biology experimental technology has provided a powerful tool for understanding the pathogenesis of pCCA and subsequent clinical transformation. A number of studies have focused on gene modification, such as the promoter methylation and histone deacetylation of pCCA related genes[11]. Non-coding RNAs also play an important role in the occurrence and development of pCCA[12]. The development of whole genome sequencing technology has accelerated the research on the evolution of pCCA. The molecular targets in pCCA are summarized in Table 1.

Table 1 Molecular targets in perihilar cholangiocarcinoma.

Genes	Full name	The role in tumor
PKM2	Pyruvate kinase M2	Oncogene
PRR11	Proline rich 11	Oncogene
TCF7	Transcription factor 7	Oncogene
HMGB1	High mobility group box 1	Oncogene
HDGF	Hepatoma-derived growth factor	Oncogene
PRDX1	Peroxiredoxin 1	Oncogene
DKK1	Dickkopf WNT signaling pathway inhibitor 1	Oncogene
ADAM17	A disintegrin and metalloproteinase 17	Oncogene
Il-8	Interleukin 8	Oncogene
CUL4A	Cullin 4A	Oncogene
MTSS1	Metastasis associated lung adenocarcinoma transcript 1	Tumor suppressor gene
RECK	Reversion-inducing-cysteine-rich protein with kazal motifs	Tumor suppressor gene
SPARCL1	Secreted protein acidic and rich in cysteine-like 1	Tumor suppressor gene
MALAT1	Metastasis associated lung adenocarcinoma transcript 1	Tumor suppressor gene

Genetic and molecular profiling of pCCA has identified a number of key abnormalities that drive tumor growth and spread, including pyruvate kinase M2 (PKM2), proline rich 11 (PRR11), transcription factor 7 (TCF7), etc. PKM2 is overexpressed in cholangiocarcinoma[13]. PKM2 overexpression is highly correlated with syndecan 2 expression and nerve invasion[14]. Silencing of endogenous PRR11 in cholangiocarcinoma cells inhibited cell proliferation, cell migration, and tumor formation ability in vivo[15]. Microarray analysis revealed that a variety of genes involved in cell proliferation, cell adhesion, and cell migration were altered in PRR11 knockout cells, including vimentin, ubiquitin carboxy terminal hydrolase 1, early growth response protein, and amino acid transporter 1 system (SNAT1). Liu et al[16] used exome and transcriptome sequencing methods to screen potential biomarkers of pCCA, and used quantitative reverse transcription polymerase chain reaction, Western blotting and immunohistochemistry methods to verify, and screened the TCF7. TCF7 expression is upregulated in pCCA, which is a biomarker of poor prognosis[17]. C-myc is the main effector of TCF7 in pCCA, regulating TCF7 to induce cell proliferation, invasion, and migration. Phosphorus like antigen 1 (FOSL1) is considered to be a downstream target of TCF7 and is required for TCF7 induced proliferation of pCCA[16]. In patients with pCCA, the triple positive expression of TCF7, c-myc and FOSL1 was more predictive of prognosis than the expression of TCF7 alone. The detection of TCF7, c-myc and FOSL1 in pCCA is helpful to screen high-risk pCCA patients with poor prognosis. TCF7 or its downstream effectors may be a promising potential target for the treatment of pCCA.

Mutations in genes such as KRAS, TP53, and SMAD4 have been found to be common in pCCA, and aberrant activation of signaling pathways such as the MAPK and PI3K/AKT pathways have also been implicated in tumor growth and progression[18]. In addition, alterations in DNA repair pathways and chromatin remodeling genes have been identified as potential drivers of cholangiocarcinoma development. pCCA is a rare and aggressive malignancy that arises from the bile ducts at or near the confluence of the right and left hepatic ducts, which is associated with a poor prognosis due to its aggressive nature and tendency to spread rapidly. Traditional treatment options for pCCA have included surgery, chemotherapy, and radiation therapy, but outcomes have been largely unsatisfactory due to the high rates of recurrence and metastasis. Recent advances in understanding the genetic and molecular features of pCCA have opened up new opportunities for targeted therapies and personalized treatment approaches.

Comprehensive genomic analyses have identified several key findings. High frequency somatic mutations in genes have been observed in pCCA tumors. The genetic and molecular features have provided new insights into the biology of pCCA and have led to the development of targeted therapies that aim to exploit specific vulnerabilities in tumor cells. In addition to targeted therapies, immunotherapy has emerged as a promising treatment approach for pCCA based on the presence of immune infiltrates in the tumor microenvironment. Checkpoint inhibitors have shown activity in other solid tumors and are being evaluated in clinical trials for pCCA[19]. Early results have been encouraging, with some patients experiencing durable responses and improved survival. In conclusion, the treatment of pCCA based on genetic and molecular features holds great promise for improving outcomes for patients with this challenging disease. However, it calls for more rigorous research to fully understand these interventions' mechanisms and their direct benefits for pCCA patients.

CLINICAL IMPLICATIONS

Despite these advances, treatment of pCCA based on genetic and molecular features remains a complex and challenging task. Tumor heterogeneity, clonal evolution, and the development of resistance mechanisms all pose significant obstacles to effective treatment. Multidisciplinary approaches that combine surgery, chemotherapy, radiation therapy, targeted therapies, and immunotherapy are likely to be needed to achieve optimal outcomes for patients with pCCA. pCCA is still hard to treat, and individualized anticancer treatment is required, which is supposed to be according to the genetic and molecular features[20].

CONCLUSION

pCCA has specific genetic and molecular features that can be used to develop personalized treatment plans. Personalized treatment approaches offer new opportunities for effectively targeting the underlying drivers of tumor growth and progression. Further research and clinical trials are needed to validate these approaches and optimize treatment strategies for pCCA. The potential for precision medicine should be explored to improve outcomes for patients with this challenging disease. The findings highlight the importance of understanding the genetic and molecular features of pCCA for developing personalized treatment strategies.