Tobacco Smoke and Head & Neck Cancer: A Deep Dive into Genetic Damage

Introduction: The Hidden Molecular Damage of Tobacco Smoke

Tobacco smoking is a leading but preventable cause of different types of cancers worldwide. Head and neck cancer (HNC) affects thousands worldwide, with tobacco smoke being one of its leading causes. But how exactly does smoking damage DNA and lead to cancer? A groundbreaking study by Torrens et al. (2025) published in Nature Genetics reveals the complex ways tobacco smoke induces genetic mutations, offering new insights into cancer development and prevention. They conducted a comprehensive analysis of 265 whole-genome sequenced head and neck cancer (HNC) cases across eight countries. Their findings uncover the intricate mutational signatures and genomic damage caused by tobacco smoke, providing critical insights into the mechanisms that drive cancer in different regions of the head and neck.

What Was the Problem? Understanding the Genetic Chaos Behind HNC

Torrens et al. (2025) set out to uncover how tobacco exposure leads to mutations in HNC and whether other factors, like alcohol or HPV, play a role. Despite being strongly linked to lifestyle factors like smoking and drinking, head and neck cancers have remained genomically underexplored. Past research lacked the full genomic scope and geographical diversity to understand how tobacco specifically alters DNA. This study sought to address this gap by identifying tobacco-induced mutational patterns across different cancer subsites and populations.

How Was the Study Conducted? Global Genomes, Tobacco Smoke-Induced Mutations

Torrens et al. (2025) analyzed 265 whole-genome sequenced HNC samples from patients across eight countries (e.g., Brazil, Italy, Argentina), ensuring diverse genetic and environmental influences. Here’s how they did it:

1. Sample Collection & Sequencing
   1. Tumor and blood samples, to accurately distinguish somatic mutations, were collected from patients with confirmed HNC. Cases included cancers from oral cavity, larynx, oropharynx, and hypopharynx.
   2. Whole-genome sequencing was performed to identify mutations linked to tobacco and alcohol exposure.
2. Sequencing Depth:
   • An average coverage of 55x for tumors and 27x for blood samples ensured robust detection.
3. Mutational Signature Analysis
   • The team used SigProfilerExtractor and mSigHdp to detect distinct mutation patterns caused by tobacco, alcohol, and other exposures.
   • Six tobacco-associated mutational signatures were identified, including some never reported before.
4. Copy Number Alterations
   • They analyzed structural changes in DNA, revealing how tobacco exposure leads to genomic instability.
5. Comparing Risk Factors
   • The study examined how smoking, alcohol, and HPV infection interacted to influence mutation rates.
   • Statistical models assessed whether alcohol enhanced tobacco’s carcinogenic effects.
6. Statistical Modeling: 
   • Signatures were cross-analyzed with lifestyle factors using regression analysis and timing of mutations.

Key Findings: How Tobacco Smoke Damages DNA

Torrens et al. (2025) identified six distinct tobacco-related mutational signatures, including three novel ones (Table 1):

1. Tobacco Causes Multiple Mutation Types
   • The study identified six distinct tobacco-related mutational signatures, each linked to different carcinogens in smoke.
   • Signature SBS4 (linked to benzo[a]pyrene) was common in larynx cancer, while SBS_I (a new signature) appeared in oral cavity tumors. SBS_I: A newly discovered signature, rich in T>A substitutions, prominent in oral cavity cancers.
   • SBS92: Previously known, found mainly in larynx and hypopharynx cancers.
   • DBS2, DBS6, ID3: Associated with tobacco, show complex double- and small indel mutations.
2. Alcohol Amplifies Tobacco’s Effects
   • Cases with both smoking and drinking showed stronger mutation patterns than those exposed to just one.
   • This suggests alcohol may enhance tobacco’s DNA-damaging effects.
3. HPV Infection Changes Mutation Patterns
   • HPV-positive tumors had fewer tobacco-related mutations, implying the virus drives cancer differently than smoking.
4. Geographical & Anatomical Differences
   • Countries with higher smoking rates had more tobacco-linked mutations.
   • The larynx was more vulnerable to tobacco damage than the oral cavity.

Interestingly, laryngeal cancers had the highest mutation burden, even after correcting for smoking status. Oral cavity cases showed distinct damage patterns, likely due to different tissue-specific enzyme activities that process tobacco carcinogens.Additionally, the study found strong correlations between tobacco-related signatures and key driver gene mutations such as TP53 and MYC, which are known to promote genomic instability.

Table 1: Comparative Distribution of Tobacco-Associated Mutational Signatures Across HNC Subsites
Subsite	SBS4 Presence (% of cases)	SBS92 Presence (% of cases)	SBS_I Presence (% of cases)	Associated Tobacco Signature Trend
Oral Cavity (OC)	17.3%	17.3%	60.6%	Predominantly SBS_I; low SBS4
Oropharynx (OPC)	17.4%	Moderate	Moderate	Mixed profile with lower tobacco signature
Hypopharynx (HPX)	52.9%	High	Low	High SBS4 and SBS92 burden
Larynx (LYX)	66.7%	High	60.2%	High burden of all major tobacco signatures

Note: SBS4 is linked to BaP exposure (C>A), SBS92 to nitrosamines (T>C), and SBS_I is novel (T>A-rich), possibly due to adenine adducts.

Why Does It Matter? Smoking’s Genetic Impact is Deeper Than We Thought

This study emphasizes that tobacco smoking doesn’t just cause cancer — it triggers multiple, distinct genetic attacks depending on where the cancer forms. For example:

• Larynx cancers exhibited high C>A mutations tied to BaP (a tobacco carcinogen).
• Oral cavity cancers were more influenced by T>A mutations from nitrosamine exposure.

Moreover, copy number analysis revealed tobacco’s link to chromosomal instability, with profound implications for tumor behavior, treatment resistance, and patient outcomes. Mutations in TP53 and gains in oncogenes like MYC and FADD were more prevalent among smokers (Table 2).

1. Personalized Prevention Strategies
   • Understanding mutation patterns could help identify high-risk individuals before cancer develops.
2. Better Treatment Approaches
   • Knowing which mutations are caused by tobacco vs. HPV could guide targeted therapies.
3. Public Health Implications
   • The findings reinforce the dangers of smoking and alcohol, supporting stricter regulations.

Table 2: Influence of Risk Factor Combinations on Driver Mutation Patterns in HNC
Exposure Type	TP53 Mutation Frequency	CASP8 Mutation Frequency	Associated Copy Number Profile	Signature Enrichment
Tobacco Only	68.8%	Low (~6%)	High copy number burden (P clusters)	SBS4, SBS92, SBS_I, DBS2, ID3
Alcohol Only	71.4%	Moderate	Mostly diploid or D2	SBS16, ID11, DBS4
Tobacco + Alcohol	87.0%	Low	Polyploid, chromosomal instability (P2)	All above (synergistic effect)
No Known Exposure	55.6%	High (~20%)	Copy-neutral, diploid (D2 cluster)	Enriched in unknown DBS_D, ID4

Note: Combined tobacco and alcohol exposure shows strongest mutation burden and highest TP53 mutation rate. CASP8 enrichment is unique to unexposed individuals.

Future Research Directions

Torrens et al. (2025) recommend the following key areas for future investigation:

1. Investigate how additional factors (e.g., diet, pollution, alcohol, HPV infections) interact with tobacco exposure.
2. Explore therapies that target specific mutation pathways induced by tobacco.
3. Examine tissue-specific metabolic responses to tobacco.
4. Study mutational signatures in non-smokers to uncover unknown environmental carcinogens.
5. Expand research to underrepresented populations for broader and more inclusive insights.

Implications for Public Health and Precision Medicine

The study provides:

1. New Biomarkers: Tobacco-related mutational signatures can help trace cancer origins and refine diagnostics.
2. Geographical Relevance: High tobacco mutation burdens matched with higher cancer rates in countries like Brazil and Romania.
3. Risk Stratification: Genetic profiles can inform treatment decisions and patient monitoring.

Conclusion: Smoke Signals in Our DNA

This landmark study provides the most comprehensive insight to date into how tobacco smoke causes genetic damage in head and neck cancers. By identifying distinct mutational signatures and region-specific driver genes, it enhances our understanding of tobacco-induced carcinogenesis. These findings pave the way for improved early detection methods and personalized treatments. The overarching message is clear: quitting smoking remains one of the most effective strategies to reduce cancer risk (image 1).

Research-Based Post for Public Awareness

This Post is Purely Based on Published Scientific Research, With All Findings and Claims Properly Cited From the Original Article. We Share This Information Solely for the Purpose of Public Awareness.

Reference: For more details, read the full study

Perdomo, S., et al. (2025). The complexity of tobacco smoke-induced mutagenesis in head and neck cancer. Nature Genetics, 57, 884–896. https://doi.org/10.1038/s41588-025-02134-0