Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics

Area of Science:

• Oncology
• Genetics
• Epigenetics

Background:

• The somatic mutation theory (SMT) has defined cancer as a genetic disease for over 30 years.
• Recent research increasingly criticizes the SMT, highlighting cancer as a complex tissue-level process.
• Genomic mutations are increasingly viewed as consequences, not primary causes, of carcinogenesis.

Purpose of the Study:

• To critique the limitations of the somatic mutation theory in explaining cancer.
• To propose epigenetics as a more logical cause of carcinogenesis.
• To present a model where microenvironmental signals induce genomic instability and epigenetic changes leading to cancer.

Main Methods:

• Review and critique of existing cancer models, focusing on the SMT.
• Analysis of the role of the tissue microenvironment in carcinogenesis.
• Examination of in vitro and in vivo studies demonstrating cancer phenotype reversion.

Main Results:

• The SMT's inadequacy in fully explaining cancer etiology is demonstrated.
• A model is presented where persistent microenvironmental signals induce genomic instability and epigenetic modifications in stem cells.
• Cancer phenotype reversion via physiological factors or drugs, without reversing key mutations, supports an epigenetic-driven model.

Conclusions:

• Epigenetic alterations, driven by the microenvironment, are a more plausible primary cause of cancer than somatic mutations.
• Genomic instability and mutations are by-products of the carcinogenic process, not its origin.
• This perspective reframes cancer development, emphasizing the role of cellular signaling and the tissue microenvironment.