Significance Of PIK3CA Mutation In Non-metastatic Colorectal Cancer

Background and Aim:Colorectal cancer(CRC)is one of the common malignant tumors in human beings,and the incidence rate of colorectal cancer ranks third and mortality rate ranks second in the world.In China,the incidence and mortality rate of colorectal cancer are on the rise.In the past decades,our understanding of colorectal cancer has been improving.However,there is still a significant proportion of patients with poor prognosis.Therefore,exploring the effects of various signaling pathways and their related genes on colorectal cancer can help improve our knowledge of colorectal cancer and improve the prognosis of colorectal cancer patients.It has been shown that the PI3K-AKT signaling pathway plays an important role in the development of colorectal cancer,breast cancer,etc.Mutations in the PIK3CA gene,a key gene in the PI3K-AKT pathway,can cause abnormal enhancement of PI3K catalytic activity and contribute to cell carcinogenesis.The effect of PIK3CA gene on colorectal cancer has been reported,however,there is still no uniform conclusion.Previous studies have focused more on metastatic colorectal cancer,and the study of PIK3CA gene in non-metastatic colorectal cancer is not well established.Moreover,there are few studies on mutations in common exon 9 and exon 20 of PI3KCA gene in non-metastatic colorectal cancer.Therefore,in this study,we conducted a joint study on the role of the PIK3CA gene and its commonly mutated exons in non-metastatic colorectal cancer based on the TCGA and our data,aiming to investigate the occurrence and significance of the PIK3CA gene in non-metastatic colorectal cancer.Method:1.The clinical data and gene expression data of colorectal cancer patients were downloaded from the TCGA database,and non-metastatic colorectal cancer cases were screened out.The mutation rate of PIK3CA and the mutation rate of each exon were calculated.To assess the association of PIK3CA mutations with clinicopathological characteristics in non-metastatic colorectal cancer.Meanwhile,for the exons with the top two mutation rates(exon 9 and exon 20),their associations with clinicopathological characteristics in non-metastatic colorectal cancer were analyzed respectively.The prognosis of PIK3CA mutations in non-metastatic colorectal cancer,non-metastatic colon cancer,and non-metastatic rectal cancer were analyzed separately.The impact of the top three exons(exons 1,9,and 20)on the prognosis of non-metastatic colorectal cancer were analyzed respectively.2.According to the inclusion and exclusion criteria,the relevant information of patients with non-metastatic colorectal cancer in our hospital from December 2014 to December 2021 was collected and followed up for survival,and we also performed PIK3CA gene testing on these 655 patients with non-metastatic colorectal cancer.The PIK3CA mutation rate and the mutation rate of each exon were calculated.To assess the association of PIK3CA mutations with clinicopathological characteristics in non-metastatic colorectal cancer.Also for exons 9 and 20,their associations with clinicopathological characteristics in non-metastatic colorectal cancer were analyzed,respectively.To analyze the prognosis of PIK3CA mutation in non-metastatic colorectal cancer,non-metastatic colon cancer,and non-metastatic rectal cancer.The prognostic impact of exons 9 and 20 on non-metastatic colorectal cancer was analyzed separately.Results:1.In the TCGA dataset,the mutation rate of PIK3CA gene was 26.3%in non-metastatic colorectal cancer,30.0%in non-metastatic colon cancer,and only 15.7%in non-metastatic rectal cancer.In non-metastatic colorectal cancer,exons 9,20 and 1 had the top three mutation rates of 10.3%,7.1%and 5.6%,respectively.Further analysis revealed that E545K and E542K in exon 9,H1047R in exon 20,and R88Q in exon 1 were a few hot spots mutations with high mutation frequency.Further analysis revealed statistical differences between the PIK3CA gene mutation group and the wild group in tumor site(p=0.003),TNM stage(p=0.011),and regional lymph node metastasis(p=0.011)in patients with non-metastatic colorectal cancer.There was a statistical difference between the exon 9 mutation group and the wild group in tumor site(p=0.038).There were statistically significant differences between the exon 20 mutation group and the wild group in tumor site(p=0.002)and regional lymph node metastasis(p=0.045).Kaplan-Meier analysis showed that in non-metastatic colorectal cancer,there was no significant difference in overall survival(OS)between the PIK3CA mutation group and the wild group(p=0.753);in non-metastatic colon cancer,the OS was also not significantly different between the PIK3CA mutation group and the wild group(p=0.836);similarly,in non-metastatic rectal cancer,OS was not significantly different between the PIK3CA mutation group and the wild group(p=0.963).Specifically for exons 1,9 and 20,in non-metastatic colorectal cancer,there was no significant difference in OS between the exon 1 mutation group and the wild group(p=0.402);no significant difference in OS between the exon 9 mutation group and the wild group(p=0.585);and no significant difference in OS between the exon 20 mutation group and the wild group(p=0.386).2.In our dataset,the mutation rate of PIK3CA gene was 7.8%in non-metastatic colorectal cancer,9.4%in non-metastatic colon cancer,and 4.6%in non-metastatic rectal cancer.In non-metastatic colorectal cancer,the mutation rate of exon 9 was 2.9%,and the mutation rate of exon 20 was 4.9%.There were statistical differences between the PIK3CA mutation group and the wild group in non-metastatic colorectal cancer patients in terms of age(p=0.032),tumor site(p=0.029),TNM stage(p=0.019)and regional lymph node metastasis(p=0.007).There were no statistical differences between the exon 9 mutation group and the wild group in age,tumor site,regional lymph node metastasis,TNM stage and other clinicopathological characteristics.There were statistically significant differences between the exon 20 mutation group and the wild group in age(p=0.001),tumor site(p=0.029),TNM stage(p=0.001),and regional lymph node metastasis(p=0.015).Kaplan-Meier analysis showed no significant differences in OS between the PIK3CA mutation group and the wild group in non-metastatic colorectal cancer(p=0.567);in non-metastatic colon cancer,there was also no significant difference between PIK3CA mutation and OS(p=0.531);the same result was found in non-metastatic rectal cancer,with no significant difference in OS between the PIK3CA mutation group and the wild-type group(p=0.774).Specifically for exons,in non-metastatic colorectal cancer,there was no significant difference in OS between the exon 9 mutation group and the wild group(p=0.354).There was also no significant difference in OS between the exon 20 mutation group and the wild group(p=0.895).Conclusion:1.PIK3CA mutation is not associated with prognosis in patients with non-metastatic colorectal cancer.2.In non-metastatic colorectal cancer,PIK3CA mutation is associated with age,tumor site,TNM stage and regional lymph node metastasis.3.PIK3CA exon 9 mutation is associated with tumor site in non-metastatic colorectal cancer.4.In non-metastatic colorectal cancer,PIK3CA exon 20 mutation is associated with age,tumor site,TNM stage and regional lymph node metastasis.