Scholarlink

<p>Alcohol consumption is a major risk factor for cancer, particularly of the head and neck. Acetaldehyde, the main ethanol metabolite, is linked to oral carcinogenesis, but the mechanisms are not well understood. While some mutational signatures such as single-base substitution signature SBS16, doublet-base substitution signature DBS4, and indel signature ID11 have been linked to alcohol use, they are not limited to alcohol-related cancers. We examined the genome-wide <i>in vivo</i> mutation landscapes of rats chronically exposed to ethanol or acetaldehyde, focusing on head-and-neck tumors (involving the cheek and the Zymbal gland) and tumors of the forestomach and liver. Mutational signature analysis revealed early-onset, exposure-associated formation of signature SBS17 in ~ 38% of head-and-neck tumors, suggesting inflammation and oxidative damage may mediate carcinogenesis in these sites. We observed relative enrichment of driver-like mutations in <i>Tp53</i>, <i>Mtor</i> and <i>Hras</i> in exposed tumors, where all <i>Tp53</i>-mutated tumors were SBS17-positive, recapitulating a similar scenario from human gastro-esophageal adenocarcinomas. Next, the doublet-base, indel, copy number and structural variant changes were sporadic and not following exposure-specific patterns. No signatures previously associated with alcohol consumption in humans were observed in the exposed animals. Thus, in this animal cancer model, alcohol-related carcinogenesis across multiple organs is unlikely to be driven mainly by direct mutagenicity of ethanol or acetaldehyde. Rather, the results support a role for non-mutational processes in mediating their carcinogenic effects. Further investigation is warranted to clarify the relationship between mutational signature SBS17 and <i>TP53</i> loss-of-function mutations as potential biomarkers of alcohol-related carcinogenesis in animals and humans.</p> Graphical Abstract <p>Ethanol or acetaldehyde exposure in rats induces limited genome-wide mutations in head-and-neck, forestomach, and liver tissues.</p> <p>SBS17 appears early in 38% head-and-neck tumors following exposure, implicating inflammation and oxidative damage.</p> <p><i>Tp53</i>, <i>Mtor</i>, and <i>Hras</i> mutations are enriched upon exposure, with all <i>Tp53</i>-mutant tumors SBS17-positive, paralleling human cancer observations.</p> <p>Exposure-linked carcinogenesis is unlikely driven by direct mutagenicity of ethanol/acetaldehyde.</p> <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Effects of ethanol and acetaldehyde on multi-organ genomic mutation landscapes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月20日

查看全文
  • Bérénice Chavanel,
  • Eva Tibaldi,
  • François Virard,
  • Christine Carreira,
  • Sergey Senkin,
  • Behnoush Abedi-Ardekani,
  • Vincent Cahais,
  • Michael Korenjak,
  • Zdenko Herceg,
  • Silvia Balbo,
  • Daniele Mandrioli,
  • Jiri Zavadil

摘要

Alcohol consumption is a major risk factor for cancer, particularly of the head and neck. Acetaldehyde, the main ethanol metabolite, is linked to oral carcinogenesis, but the mechanisms are not well understood. While some mutational signatures such as single-base substitution signature SBS16, doublet-base substitution signature DBS4, and indel signature ID11 have been linked to alcohol use, they are not limited to alcohol-related cancers. We examined the genome-wide in vivo mutation landscapes of rats chronically exposed to ethanol or acetaldehyde, focusing on head-and-neck tumors (involving the cheek and the Zymbal gland) and tumors of the forestomach and liver. Mutational signature analysis revealed early-onset, exposure-associated formation of signature SBS17 in ~ 38% of head-and-neck tumors, suggesting inflammation and oxidative damage may mediate carcinogenesis in these sites. We observed relative enrichment of driver-like mutations in Tp53, Mtor and Hras in exposed tumors, where all Tp53-mutated tumors were SBS17-positive, recapitulating a similar scenario from human gastro-esophageal adenocarcinomas. Next, the doublet-base, indel, copy number and structural variant changes were sporadic and not following exposure-specific patterns. No signatures previously associated with alcohol consumption in humans were observed in the exposed animals. Thus, in this animal cancer model, alcohol-related carcinogenesis across multiple organs is unlikely to be driven mainly by direct mutagenicity of ethanol or acetaldehyde. Rather, the results support a role for non-mutational processes in mediating their carcinogenic effects. Further investigation is warranted to clarify the relationship between mutational signature SBS17 and TP53 loss-of-function mutations as potential biomarkers of alcohol-related carcinogenesis in animals and humans.

Graphical Abstract

Ethanol or acetaldehyde exposure in rats induces limited genome-wide mutations in head-and-neck, forestomach, and liver tissues.

SBS17 appears early in 38% head-and-neck tumors following exposure, implicating inflammation and oxidative damage.

Tp53, Mtor, and Hras mutations are enriched upon exposure, with all Tp53-mutant tumors SBS17-positive, paralleling human cancer observations.

Exposure-linked carcinogenesis is unlikely driven by direct mutagenicity of ethanol/acetaldehyde.