Cellular Etiology of Skin Nodules and Growths
Yes, skin nodules and growths fundamentally arise from errors in DNA replication during cell division, though the specific mechanisms vary depending on whether the growth is benign or malignant. 1
DNA Replication Errors as the Foundation
DNA polymerases that replicate DNA during the S-phase of the cell cycle are inherently error-prone, producing single-nucleotide variations from base incorporation errors and insertions/deletions from polymerase slippages. 1 These replication errors are normally corrected by two key systems:
- The exonuclease proofreading domains of DNA polymerases 1
- The mismatch repair (MMR) system (involving MSH2, MSH6, MLH1, and PMS2 genes) 1
When these repair mechanisms fail, mutations accumulate progressively with each cell division, eventually leading to abnormal growths. 1
Mechanisms of Abnormal Growth Formation
Benign Lesions
Benign skin growths typically result from localized proliferative errors without the aggressive mutation accumulation seen in malignancies. 2 The cellular basis includes:
- Vascular proliferation errors - as seen in infantile hemangiomas, where endothelial cell replication produces benign vascular tumors that typically involute spontaneously 2
- Melanocytic proliferation - producing nevi through controlled melanocyte replication errors that remain stable 2
Malignant Transformations
Malignant skin lesions develop when DNA replication errors overwhelm repair capacity, leading to progressive mutation accumulation. 1 This occurs through:
- Cumulative DNA damage during cell division - aneuploidy (abnormal DNA content) occurs increasingly in higher-grade keratinocytic intraepidermal neoplasias, indicating progressive damage accumulation 3
- Loss of repair fidelity - errors in DNA methylation re-establishment after replication contribute to cellular aging and malignant transformation 1
- Mitotic age accumulation - each cell division introduces small methylation errors that compound over time 1
Inherited vs. Acquired Replication Defects
Germline Mutations
Individuals with inherited defects in DNA repair genes face dramatically accelerated mutation accumulation. 1
- Constitutional mismatch repair deficiency (CMMRD) - biallelic MMR gene mutations cause one of the most aggressive childhood cancer syndromes, with median tumor onset at 7.5 years due to rapid mutation accumulation 1
- Lynch syndrome - heterozygous MMR mutations lead to adult-onset cancers through slower but persistent replication error accumulation 1
Acquired Defects
Most skin growths result from acquired somatic mutations that accumulate during normal aging and environmental exposures. 1
- Replication-associated errors increase with cell turnover - inflammatory conditions and cellular damage that increase division rates accelerate mutation accumulation 1
- UV-induced DNA damage compounds replication errors in sun-exposed skin 4
Clinical Implications
The cellular etiology directly impacts growth behavior and malignant potential:
- Hyperproliferation markers (Ki67 expression) correlate strongly with progression from benign to malignant lesions, reflecting increased replication error rates 3
- Aneuploidy frequency increases with lesion grade, demonstrating cumulative replication damage 3
- Multiple synchronous lesions (as in CMMRD patients developing >100 colonic polyps) reflect systemic replication repair deficiency 1
Critical Pitfall
Not all malignant lesions progress through serial stages of increasing dysplasia - the lower aneuploidy frequency in microinvasive squamous cell carcinoma compared to high-grade intraepithelial neoplasia suggests alternative pathways to invasion beyond simple accumulation of replication errors. 3 This indicates that some malignancies may arise through different mechanisms or accelerated pathways that bypass intermediate stages.