Genetic mutations in smoking-associated prostate cancer

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• Tobacco smoking is a known risk factor for various cancers, including prostate cancer (PCa).
• Genetic predispositions can influence cancer development and progression.
• Understanding the interplay between smoking, genetic mutations, and PCa outcomes is crucial for personalized medicine.

Purpose of the Study:

• To compare gene mutation frequencies between smokers and nonsmokers with PCa.
• To identify specific genetic mutations associated with smoking and PCa.
• To investigate the correlation between smoking, gene mutations, and overall survival in PCa patients.

Main Methods:

• Analysis of the American Association for Cancer Research Project GENIE registry data.
• Inclusion of 1832 PCa patients categorized as smokers and nonsmokers.
• Comparison of mutation frequencies (point mutations, copy number variations, structural variants) in 47 genes using next-generation sequencing and logistic regression analysis.

Main Results:

• Smokers exhibited a significantly higher mutation frequency (47.6%) and tumor mutational burden compared to nonsmokers (41.3%).
• Specific genes like PREX2, PTEN, AGO2, and KMT2C showed higher mutation rates in smokers, while APC and KMT2A mutations were more frequent in nonsmokers.
• Smoking history, metastatic disease, and PTEN somatic gene mutation were independent predictors of increased overall mortality in PCa patients.

Conclusions:

• Prostate cancer patients with a smoking history have a higher frequency of somatic genetic mutations.
• PTEN somatic gene mutation is associated with increased overall mortality in PCa, irrespective of smoking status.
• Specific PTEN mutations (G129R and K267Rfs*9) were characteristically detected in smokers and nonsmokers, respectively, offering insights into smoking-related PCa mechanisms.