Related Experiment Video
Updated: May 23, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
APOBEC affects tumor evolution and age at onset of lung cancer in smokers
Tongwu Zhang1, Jian Sang1, Phuc H Hoang1
1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.
Insights
Lung cancer subtypes show distinct APOBEC mutagenesis patterns. High APOBEC3A (A3A) activity correlates with TP53 mutations and progenitor cells, while APOBEC3B (A3B) links to KRAS mutations in smokers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Somatic mutations from APOBEC3A (A3A) and APOBEC3B (A3B) are common in solid tumors.
- The impact of A3A/B enzymes on tumor evolution alongside external mutagens is not well understood.
Purpose of the Study:
- To investigate how APOBEC mutagenesis subtypes influence lung cancer development in smokers.
- To characterize the distinct genomic and cellular features of these subtypes.
Main Methods:
- Multi-omics profiling of 309 lung cancers from smokers.
- Analysis of mutation patterns, including APOBEC3A-like and APOBEC3B-like signatures.
- Comparison of tumor subtypes based on APOBEC mutagenesis levels (LAS vs. HAS).
Main Results:
- Two lung cancer subtypes identified: Low APOBEC Signature (LAS) and High APOBEC Signature (HAS).
- LAS tumors showed A3B-like mutagenesis, KRAS mutations, and were linked to smoking.
- HAS tumors exhibited A3A-like mutagenesis, TP53 mutations, older age at onset, progenitor cells, more neoantigens, and distinct signaling pathways.
Conclusions:
- APOBEC mutagenesis heterogeneity, combined with smoking and cell type, drives lung cancer evolution.
- Distinct APOBEC signatures (A3A vs. A3B) define tumor subtypes with different characteristics and origins.
- Findings highlight the interplay between endogenous mutational processes and external factors in cancer development.
More Related Videos
Related Concept Videos
01:25Statistical Methods for Analyzing Epidemiological Data
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
02:59Cancer Prevention
Some...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:21Cancer Survival Analysis
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...