Effects of Co-occurring Genomic Alterations on Survival in Patients with KRAS-Mutant Pancreatic Cancer Co-occurring Alterations on Survival in Patients

categories of molecules responsible for cell adhesion, cell communication, and cell growth/maintenance. The following study analyzes the relationship between mutations in the co-occurring genes and the development of pancreatic cancer. We then explore the effects of co-mutations on patient survivability and on various other pathways. Discussion The study found the various effects of co-occurring genomic alterations on survival in patients with KRAS-Mutant Pancreatic cancer. The study analyzes the genetic heterogeneity with respect to cancer-related co-mutations and their correlation with KRAS ABSTRACT Pancreatic Cancer is one of the most malignant cancers with a high mortality rate. Although the effects of mutant-KRAS gene have been highly studied in the past, the effects of genes co-mutated with mutant KRAS lack a clear explanation. The study reveals that co-mutating genes also hold a significant role in inducing pancreatic cancer in patients, specifically divided into three classes of groups: cell adhesion, cell growth/maintenance, and cell communication. The KRAS mutation may co-occur with other gene-mutations, resulting in the effects of mutant-KRAS on patient survival to be compounded by the presence of co-occurring genomic mutations. Our study reveals that amongst the categories of co-mutated genes, cell communication is found to hold the most severe effect on patient survivability As the of may describe different biological subsets of patients with KRAS-mutant we explored the effects of co-occurring mutations on patient survival rates. Our results, based on 1207 patient samples from 10 different studies, show that a total of 306 co-occurring mutations occur in patients with KRAS-mutant pancreatic cancer. Further analysis was performed by utilizing the Fun Rich tool, categorizing the 306 co-occurring genes into three biological/molecular groups to analyze the distinct effects each group holds to the survivability of pancreatic cancer patients.


Introduction
Pancreatic cancer, including Pancreatic Adenocarcinoma and PNET (Pancreatic Neuroendocrine Tumor), is known to be one of the most common and deadly cancers [1] in our society. Numerous studies [2] have shown a strong relationship between mutations in the KRAS gene, a gene that codes for a protein that regulates the While the significance of KRAS and its mutant form in promoting pancreatic cancer is heavily studied, there have been few studies analyzing the role of genes that co-occur with mutant-KRAS.
Although mutant KRAS has been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated pancreatic cancer represents a genetically heterogeneous subgroup, specifically divided into categories of molecules responsible for cell adhesion, cell communication, and cell growth/maintenance. The following study analyzes the relationship between mutations in the co-occurring genes and the development of pancreatic cancer. We then explore the effects of comutations on patient survivability and on various other pathways.

Discussion
The study found the various effects of co-occurring genomic alterations on survival in patients with KRAS-Mutant Pancreatic cancer. The study analyzes the genetic heterogeneity with respect to cancer-related co-mutations and their correlation with KRAS mutation. As the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant pancreatic cancer, we explored the effects of co-occurring mutations on patient survival rates. Our results, based on 1207 patient samples from 10 different studies, show that a total of 306 co-occurring mutations occur in patients with KRAS-mutant pancreatic cancer. Further analysis was performed by utilizing the Fun Rich tool, categorizing the 306 co-occurring genes into three biological/molecular groups to analyze the distinct effects each group holds to the survivability of pancreatic cancer patients.

Cell Communication
Among the 306 genes found to be co-mutated with mutant-KRAS, CDKN2A, the gene that encodes p16lNK4A, was found to hold a significant role in the progression of the cell cycle ( Figure 5). The

Cell Growth and Maintenance
We researched 7 genes (ASTN1, SYNE1, MYO18B, DNAH7, DYNC2H1, LAMA1) which have mutation tendency more than 2% among 36genes co-mutated with KRAS. We find out that all genes do not have enough information with cancer or direct relation with pancreatic cancer, but only MYO18B was related to lung cancer.
MY018B is a candidate tumor suppressor gene at chromosome 22q12.1, deleted, mutated, and methylated in human lung cancer.
Restoration of MYO18B expression in lung carcinoma suppressed anchorage-independent growth [1]. Therefore, if MYO18B is mutated, it may not play a role as a tumor suppressor anchorageindependent growth of the tumor can be activated. Survival rate of patients with co-occurring gene mutations of cell growth/ maintenance and KRAS was higher than the survival rate of those without. However, the data on gene mutation was insufficient in finding the exact relation of mutation and cancer.

Cell Adhesion
Fun Rich analysis revealed the presence of 25 genes of the cell adhesion group to be co-mutated with mutant-KRAS. EMT

Pathway Analysis by KEGG Mapper
The KEGG PATHWAY database is deployed as a web application for pathway diagrams. The genes resulting from Funrich were analyzed by the search pathway tool to overlay the co-occurring mutant gene with KRAS-mutation onto biochemical pathways provided by KEGG. We were able to find 25, 36, and 90 genes, respectively, in these three separate categories. The results of the data analysis prove to be significant as the P-value acquired from the analysis was all set     The pathway analysis displays two significantly affected pathways in pancreatic cancers: the cell cycle and the Wnt signaling pathway. KEGG (Kyoto Encyclopedia of Genes and Genomes), a collection of databases containing genomes, biological pathways, and diseases, was used to analyze the pathway data. KEGG is utilized for bioinformatics research and education, including data analysis in omics studies. In the process of the cell cycle, activation of G1/S progression is represented. During this transition, the cell makes decisions to become quiescent (enter G0), differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. In this process, mutations of Menin, p16NK4a, and p27/Kip1 co-occur with KRAS mutation. The Wnt signaling pathway is a pathway of signal transduction that begins with proteins that pass signals into a cell through cell surface receptors.

Results
The proliferation and cell invasion can be activated by Wnt signaling and the mutations of Frizzled, APC, and β-catenin tend to co-occur with KRAS mutation during this process ( Figure 5).