As is well known, ccRCC is mainly caused by the mutation of VHL gene located on chromosome 3p25 [18]. This tumor suppressor gene plays a critical role in hypoxia response and participates in the stimulation of ccRCC oncogenesis and angiogenesis [19]. However, large scale genomic profiling studies have found large genetic heterogeneity in ccRCC. Racial diversity may be one of the main causes leading to the difference in genetic profiles. As a result, understanding the genetic landscape and discovering the discrepancies between different races are under active demand. In the two previous studies of ccRCC from Chinese patients, only the profiles of somatic gene mutations were described and their relationship with the clinical and pathological outcomes was not mentioned [13, 14]. In this research, we performed an analysis of somatic gene mutations and taking together with the previous studies in Chinese ccRCC patients, we further demonstrated a possible distinct profile of mutated genes between Chinese and Western population, which might probably indicate different biological features and diverse prognosis or treatment response in different populations. Although mutations in certain genes (e.g., VHL, BAP1, and PTEN) have been reported, our study provides new perspectives and data support in analyzing the association of these mutations with clinicopathological features in the Chinese population.
Genetic heterogeneity exists among different ethnic groups, a phenomenon that reflects a combination of biological and environmental factors. Natural selection, genetic drift, and differences in cultural practices and lifestyles are key evolutionary factors that shape these genetic differences [20,21,22]. For example, findings suggest that genome-wide variation in cytosine modifications between European and African populations can have complex effects on traits [23]. Similarly, breast cancer incidence and mortality vary among different populations. African-American, Hispanic, Asian and Native American women have lower incidence but higher mortality compared with non-Hispanic white women [24]. In future studies, in-depth exploration of these mechanisms will not only enhance our understanding of human genetic diversity, but also be important for personalized medicine for different ethnic groups. We also propose directions for future research, including conducting studies in larger ethnic groups to validate our findings and utilizing multi-omics approaches to explore the molecular mechanisms behind these genetic heterogeneities.
Since 2006, multiple antiangiogenetic drugs targeting VHL/HIF-1/VEGF pathway and MTOR inhibitors targeting PI3K/AKT/MTOR pathway have been approved for using in metastatic ccRCC sequentially [19]. However, the prognosis or the treatment response can only be predicted roughly depending on certain clinical and pathological characteristics [25]. Astonishingly, no consistent relationship has been found between VHL status and clinical outcome in metastatic ccRCC [18]. Kim et al. had a pooled meta-analysis from ten studies to evaluate the odds ratios for pathological features and hazard ratios for OS. There was no significant relationship between VHL alterations and nuclear grade, disease stage and OS [26]. So, we presume that other simultaneous or metachronous genetic mutations other than VHL gene may be present to have synergy or independent deleterious effects. Utilizing the ccRCC data of PUCH and TCGA cohort, we further analyzed the relationships between the frequently mutated genes and the clinicopathological outcomes in this study. In PUCH-ccRCC cohort, we found that BAP1 and PTEN had a significantly correlation with higher tumor grade, DNM2 had a significantly correlation with lower tumor grade. In TCGA-KIRC cohort, BAP1 and TP53 had a significantly correlation with a worse OS of ccRCC. These results indicated that the mutation of BAP1, PTEN, and TP53 might have an enhanced effect on ccRCC progression, while DNM2 might have a negative regulation on ccRCC tumor cell activity.
Previous studies have indicated that the loss of androgen receptor (AR) expression is associated with aggressive disease, whereas patients with AR-positive tumors exhibit a favorable prognosis [27]. The impact of AR on RCC progression may operate through a series of miRNAs independent of VHL status [28,29,30]. TFEB, a member of the microphthalmia transcription factor (MiT) family, is associated with RCC that often falls under the category of MiT family translocation RCC, which is less common and less aggressive compared to TFE3-fusion associated RCC. However, TFEB-rearranged RCC is associated with a more aggressive clinical course, and vascular endothelial growth factor A (VEGFA) may be linked to the aggressiveness in TFEB-rearranged RCC [31]. Despite this, TFEB proteins are involved in numerous complex molecular pathways in carcinogenesis [32]. The dynamin 2 (DNM2) gene has been found to be associated with the development and inferior outcome of leukemia [33]. We have initially explored the relationship between the aforementioned mutated genes and the clinicopathological features in ccRCC, but more in-depth specific studies are still required to elucidate their molecular biological functions.
Among these genes, BAP1 is the most frequently mutated and is located at chromosome position 3p21, adjacent to the VHL gene region. BAP1 encodes the histone deubiquitinating enzyme BRCA1-associated protein 1, which acts as a tumor suppressor [34]. Patients with BAP1-mutant ccRCC have been reported to have a poor prognosis [9, 35, 36]. BAP1 exerts its tumor suppressive activity based on its nuclear localization and deubiquitination activity, and BAP1-deficient cancer cells have been reported to be more sensitive to Olaparib and more susceptible to radiation [37, 38]. Given the high mutation rate of BAP1, BAP1-associated ccRCC in the Chinese population should garner more attention. A Phase II clinical trial (ID: NCT03207347) is currently underway to evaluate the clinical response to PARP inhibitors in patients with BAP1-mutated cancers, including RCC [39]. Based on the aforementioned results, we can infer that BAP1, PTEN, and TP53 may play significant roles in the progression of ccRCC. Patients with mutations in BAP1 or PTEN, BAP1 or TP53, may be categorized as a group of high-risk ccRCC, requiring more aggressive postoperative treatment to reduce the recurrence rate.
HMCN protein family has two close analogues (HMCN1 and HMCN2). HMCN1, produced mainly by stromal cells and usually associated with calcium binding, is a cell polarity-associated protein that may play a biological role at epithelial cell junctions [40]. HMCN1 is involved in many processes such as anchoring of mechanosensory neurons in the epidermis, stabilization of genital syncytia, and organization of hemispheric forms in the epidermis [41]. Previous studies have shown that HMCN1 can promote ovarian cancer invasion by regulating cancer-associated fibroblasts [42]. Kikutake found that HMCN1 mutant allele was strongly associated with a poorer prognosis in breast cancer patients [43]. Gong found that HMCN1 mutation might have an important clinical significance in ccRCC by using information from public databases [44]. In the present study, we verified the above points with our own sequencing data and we identified that patients with mutant type of HMCN1 had a significantly poor prognosis compared to wild-type patients in ccRCC.
To deepen our understanding of the mechanisms by which HMCN1 mutations influence ccRCC prognosis, we propose a detailed exploration of the molecular pathways affected by HMCN1. This could involve investigating the interaction between HMCN1 and other key proteins involved in cell adhesion, migration, and the tumor microenvironment. Additionally, we will examine the impact of HMCN1 mutations on the signaling pathways that regulate cell survival and apoptosis, which are critical for cancer progression.
In recent years, the dawn of the immunotherapy era has brought with it an expanding comprehension of the tumor microenvironment within RCC. Research has revealed that a prevalent, yet seemingly dysfunctional phenotype of “resident” NK cells is notably present in patients with metastatic ccRCC. This presence correlates with diminished survival rates, particularly in those with advanced stages of the disease, even amongst those undergoing treatment with immune checkpoint inhibitors (ICIs). The potential restoration of NK cell functionality emerges as a promising therapeutic avenue for individuals battling ccRCC [45]. Our current study highlights the immune cell infiltration results, which exhibit marked disparities in follicular helper T cells and CD4 naive T cells. This suggests that the mutant HMCN1 variant may amplify anti-tumor immune responses. Our discoveries offer fresh perspectives for prognostic assessment and precision therapy in ccRCC patients. Nonetheless, comprehensive research is imperative to unravel the intricate mechanisms by which HMCN1 influences ccRCC.
Our preliminary study still has some limitations. Firstly, we recognize that the original sample size was small, which limits the statistical validity and generalizability of the study. To address this issue, we are actively expanding the sample size and plan to include more patient data in future studies to improve the reliability and representativeness of the study. We plan to collect a larger sample of ccRCC patients by collaborating with other medical centers in the country. To ensure the representativeness of the sample, we will use random sampling and ensure that the sample covers different ages, genders and geographic locations. In addition, we will also ensure the diversity and breadth of the sample through multi-center collaboration. Secondly, the limitation of our study is that exploration was performed at the transcriptional level, the state of genome, translation and the alteration of the relevant pathway, are all not clear. In future studies, we plan to use proteomics techniques to analyze how these mutations affect protein expression and function. We also plan to use cellular and animal models to validate the effects of these mutations on relevant signaling pathways and their role in tumor development and drug response.
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