6. Results & Discussion
TMB and MSI plays an important role in cancer because they are prognostic biomarkers and depends upon the nature of cancer.
- A high prognostic index typically suggests a worse prognosis and a lower expected survival. In other words, a high index is associated with a higher risk of adverse outcomes or lower survival rates. A low prognostic index typically indicates a better prognosis and a higher expected survival. A low index is associated with a lower risk of adverse outcomes or higher survival rates.
So, in summary:
High Prognostic Index = Low Expected Survival
Low Prognostic Index = High Expected Survival
- High TMB has been associated with improved responses to immunotherapy in some cancer types, potentially leading to better survival rates. Tumors with high TMB may have more neoantigens, making them more recognizable to the immune system. The correlation between TMB and survival rate can be positive in the context of immunotherapy, but it can vary depending on the cancer type and other clinical factors.
High TMB = Better survival rates
Low TMB = Worse survival rates
- MSI is a marker for DNA mismatch repair deficiency and is associated with a distinct subset of cancers, such as colorectal cancer. In MSI-high tumors, there is a strong association with improved responses to immunotherapy and, consequently, better survival rates. This positive correlation is well-established in MSI-high colorectal cancer and may extend to other MSI-high tumors. TMB and MSI are distinct markers, but they can sometimes overlap. In some cases, tumors that are MSI-high may also have a high TMB. However, the two markers are not interchangeable, and a tumor can be TMB-high and MSI-stable or vice versa.
High MSI = Better survival rates
Low MSI = Worse survival rates
In our study, most of the cancer types showed that High MSI leads to poor survival rates and low MSI leads to better survival rates.
- RWR scores are used in network-based analyses to prioritize genes or pathways for their potential relevance to survival outcomes. The correlation between RWR scores and survival rate depends on the specific context and the network being analyzed. If RWR identifies critical genes or pathways associated with tumor progression or resistance to treatment, there may be a positive correlation with worse survival.
High Prognostic Index = Low Expected Survival
Low Prognostic Index = High Expected Survival
This shows that RWR is the significant feature for calculating prognostic index (PI).
Survival curves delineating the Prognostic Index across diverse cancer types reveal distinct trajectories
Survival curves of Tumor Mutational Burden (TMB) for all cancer types
Survival curves of Microsatellite Instability (MSI) for all cancer types
Survival curves of age for all cancer types
Survival curves of RWR for all cancer types
In the above all cancers, Prognostic Index (PI) concept is same. High PI gives low survival rates whereas low PI leads to high survival rates. In Breast, OV and lung cancers, high TMB leads to better survival rates while low TMB leads to low survival rates whereas MSI is high which leads to low survival rates and low MSI leads to high survival rate. According to the paper "Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis", in breast cancer, Kaplan-Meier survival analysis based on the survival package showed that the 5-year survival rate of the high TMB group was much higher than that of the low TMB group. As per the paper "Tumor mutation burden (TMB)-associated signature constructed to predict survival of lung squamous cell carcinoma patients", in lung cancer, Kaplan–Meier indicated patient OS in the low-risk group was significantly lower than in the high-risk group, as confirmed by external validation using data from the GEO database. Liu et al stated in their paper "Multi‐omics analysis of tumor mutational burden combined with prognostic assessment in epithelial ovarian cancer based on TCGA database" that Higher TMB level revealed better OS and DFS and correlated with earlier clinical stages in EOCs (P = 2.796e-04). The OS-related prognostic model constructed based on seven TRGs (B3GALT1, LIN7B, ANGPT2, D2HGDH, TAF13, PFDN4 and DNAJC19) significantly stratified EOC patients into high- and low-risk groups (P < 0.001).
In GBM cancer, the condition is reverse in case of survivability. High TMB gives low survival rate and low TMB gives high survival rate whereas high MSI leads to high survival rate and low MSI leads to low survival rate. As per the paper "Tumor mutational burden is associated with poor outcomes in diffuse glioma", TMB was higher for the group of mutant genes that are frequently mutated in glioblastomas (GBMs) and lower for the group of mutant genes that are frequently mutated in lower-grade gliomas (LGGs). Patients with a higher TMB exhibited shorter overall survival. TMB is associated with poor outcomes in diffuse glioma. The high proliferative activity in the TMB-High group could account for the shorter survival of these patients.
This concludes that in most of the cases, TMB is directly proportional to survivability and MSI is indirectly proportional to survivability. But in case of GBM, the situation is vice-versa.