Clonal Evolution

Dananberg et al. (2024) — APOBEC Mutagenesis in Cancer Development and Susceptibility

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Bibliographic Reference

Dananberg, A., Striepen, J., Rozowsky, J. S., & Petljak, M. (2024). APOBEC mutagenesis in cancer development and susceptibility. Cancers, 16(2), 374. https://doi.org/10.3390/cancers16020374

Core Argument

While APOBEC mutagenesis is detected in over 50% of cancers and is linked to tumor heterogeneity, persistent cell evolution, and therapy responses, its contribution to malignant transformation and cancer susceptibility remains poorly understood. This review synthesizes three converging lines of evidence — germline polymorphisms, somatic mutagenesis in non-malignant tissues, and in vivo transgenic models — to assess when and how APOBEC mutagenesis contributes to carcinogenesis. The tissue of origin matters enormously: APOBEC mutagenesis is present in normal lung, intestine, and bladder but absent from normal liver, endometrium, and blood, mirroring the cancer types where the signatures appear.

Methods

This is a comprehensive review synthesizing: (i) germline association studies of APOBEC locus polymorphisms (A3AB deletion, rs1014971) with cancer risk across multiple ethnicities; (ii) somatic mutational signature data from 20+ studies of non-malignant and pre-malignant human tissues (lung, intestine, bladder, esophagus, skin, colon, liver, endometrium, blood, bone marrow, placenta, prostate); and (iii) in vivo transgenic mouse models expressing APOBEC1, APOBEC3A, APOBEC3B, APOBEC3G, and other paralogs under various promoters and cancer predisposition backgrounds.

Key Findings

Germline evidence

  • A3AB deletion (29.5 kb, chr22q13.1) shows striking ethnic variation: Southeast Asian 36.9%, South American 57.7%, African 0.9%, European ~6%. Associated with increased breast and ovarian cancer risk in Asian populations; conflicting evidence in Europeans, though carriers under 50 show increased lung and prostate cancer risk. Breast cancers from carriers exhibit elevated SBS2/SBS13 burdens, higher in homozygotes. Proposed mechanisms: stabilized APOBEC3A hybrid transcript, increased APOBEC3H nuclear localization in carriers.
  • rs1014971 (allele T) located in a long-distance enhancer upstream of the APOBEC3 cluster that interacts with the APOBEC3B promoter. Associated with increased bladder cancer risk, elevated APOBEC3B expression, and higher APOBEC-signature burdens in bladder tumors. Also associated with increased breast cancer risk and APOBEC3B expression, but breast cancers from carriers do NOT show increased APOBEC mutations — possibly acting through mutagenesis-independent mechanisms.

Somatic mutagenesis in non-malignant tissues

Tissue types where APOBEC signatures are detected in normal tissue:

  • Lung bronchial epithelium: 11–78% of samples (Yoshida 2020, Li 2021)
  • Small intestine epithelium: 14–73% of samples (Moore 2021, Wang 2023)
  • Bladder urothelium: ~22% of samples (Lawson 2020)

Tissue types where APOBEC signatures are rare or absent in normal tissue:

  • Colon epithelium: 0–0.5% of samples (Lee-Six 2019, Kakiuchi 2020)
  • Esophagus epithelium: 0–28%, becoming prevalent only at HGIN stage (Chang 2023)
  • Liver parenchyma: 0% across >2,000 samples (Brunner 2019, Ng 2021)
  • Endometrium: 0% across 292 samples (Moore 2020)
  • Blood/bone marrow: 0% across >700 samples (Machado 2022, Osorio 2018)

Timing implications:

  • In esophagus, APOBEC hypermutation appears only at HGIN stage (25% of clones), AFTER TP53 biallelic loss and copy number alterations — it is a late event, not a cancer initiator.
  • In tissues where APOBEC signatures already appear in normal epithelium (lung, intestine, bladder), APOBEC mutagenesis may play an earlier role in carcinogenesis.

In vivo transgenic models

APOBEC3A:

  • Constitutive human tumor-level expression promotes colon cancer in ApcMin mice (Law 2020).
  • Hydrodynamic expression in Fah liver regeneration model drives HCC dependent on catalytic activity — critically, the other six APOBEC3 paralogs FAILED to develop tumors in this model (Law 2020, Naumann 2023).
  • Truncated APOBEC3A at physiological levels drives pancreatic cancer metastasis independent of canonical deaminase activity (Wormann 2021) — a non-mutagenic mechanism.

APOBEC3B:

  • Constitutive human tumor-level expression accelerates carcinogenesis, increases tumor heterogeneity, and promotes metastasis in older wild-type mice; all phenotypes dependent on catalytic activity (Durfee 2023).
  • In EGFR-mutant lung cancer models, APOBEC3B constrains tumorigenesis (Caswell 2023).
  • Acute overexpression causes RNA editing and lethality (de la Vega 2023).
  • Variable outcomes depending on expression level, duration, and tissue context.

APOBEC3G:

  • Promotes bladder cancer mutagenesis, genomic instability, and kataegis in BBN-induced bladder cancer model; associated with a novel SBS signature and shorter survival (Liu 2023).

APOBEC1:

  • Ectopic overexpression in mouse/rabbit liver causes hepatocellular carcinoma (Yamanaka 1995), but relevance to human cancer is uncertain as APOBEC1 is not normally expressed in human liver.

Key conclusions

  • APOBEC mutagenesis can contribute to carcinogenesis, but the extent varies dramatically by tissue type due to variable APOBEC regulation and dysregulation.
  • The timing of APOBEC activity relative to malignant transformation differs: early in lung and intestine (signatures in normal tissue), late in esophagus (after TP53 loss).
  • APOBEC3A is the most potent carcinogenic APOBEC3 in vivo — it is the only paralog that drives liver cancer in the Fah model, and it drives colon cancer in ApcMin mice.
  • APOBEC3B can promote or constrain tumorigenesis depending on context, expression level, and tissue.
  • APOBEC3G emerges as a contributor to bladder cancer mutagenesis with its own signature.
  • Current transgenic models have limitations: constitutive ubiquitous expression from heterologous promoters does not recapitulate the episodic, lineage-restricted patterns observed in human tissues.

Concepts Introduced or Used

APOBEC-mutagenesis, germline-polymorphism, cancer-susceptibility, carcinogenesis, pre-malignant, non-malignant-tissue, A3AB-deletion, rs1014971, in-vivo-models, APOBEC3A, APOBEC3B, APOBEC3G, tissue-specificity, epigenetic-regulation, somatic-mutation, kataegis, omikli

Entities Referenced

  • Polymorphisms: A3AB deletion (29.5 kb), rs1014971 (SNP, allele T), APOBEC3H haplotype I
  • Mouse models: ApcMin, Fah, Kras/Trp53, EGFRL858R, BBN bladder, Pdx1-Cre/KRAS/Tp53
  • Cancer types: breast, ovarian, bladder, lung, prostate, esophageal SCC, colon, liver, pancreatic, cervical, HNSCC, CLL, B-cell lymphoma, multiple myeloma
  • Normal tissue studies: Yoshida 2020 (lung), Li 2021 (multi-tissue), Moore 2021 (multi-tissue), Wang 2023 (small intestine), Lawson 2020 (bladder), Lee-Six 2019 (colon), Chang 2023 (esophageal pre-cancer)
  • Genes: TP53, PIK3CA, KRAS, APC, EGFR, ERCC2

Limitations (as stated by authors)

  • The review itself identifies knowledge gaps rather than providing new data: the precise mechanisms linking APOBEC germline polymorphisms to cancer risk are not well understood.
  • In vivo models do not recapitulate the episodic, lineage-restricted APOBEC activity observed in human tissues — constitutive ubiquitous expression from heterologous promoters separates expression from native regulatory mechanisms.
  • Pre-malignant tissue samples for many APOBEC-prevalent cancer types (breast, ovary) are not routinely biopsied, limiting understanding of APOBEC timing in those tissues.
  • The contribution of APOBEC mutagenesis to malignant transformation versus cancer progression remains difficult to disentangle from available data.

Relevance to Clonal Evolution

This review provides the most comprehensive synthesis to date of when and where APOBEC mutagenesis acts as an evolutionary force in cancer. The tissue-specific prevalence data — APOBEC signatures in 78% of normal bronchial samples but 0% of normal liver samples — directly informs which cancer types are likely to experience APOBEC-driven clonal-evolution from the earliest stages. The timing data from esophageal pre-cancer (APOBEC appears only at HGIN, after TP53 loss) demonstrates that APOBEC mutagenesis can be a consequence rather than a cause of clonal expansion in some tissues. The in vivo evidence that APOBEC3A drives carcinogenesis while other APOBEC3 paralogs do not provides the functional validation for the Petljak et al. (2022) cell-line finding that APOBEC3A is the main cancer mutator. The APOBEC3G bladder cancer finding extends the mutational repertoire beyond the canonical APOBEC3A/B dichotomy.

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