Steele Edward J, Lindley Robyn A
Melville Analytics Pty Ltd. and Immunomics, Kangaroo Point, Brisbane 4169, Australia.
Department Clinical Pathology, Victorian Comprehensive Cancer Centre (VCCC), University of Melbourne, Melbourne 3052, Australia.
Int J Mol Sci. 2025 Jan 24;26(3):989. doi: 10.3390/ijms26030989.
This paper provides a critical analysis of the molecular mechanisms presently used to explain transcriptional strand asymmetries of single base substitution (SBS) signatures observed in cancer genomes curated at the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Wellcome Trust Sanger Institute). The analysis is based on a deaminase-driven reverse transcriptase (DRT) mutagenesis model of cancer oncogenesis involving both the cytosine (AID/APOBEC) and adenosine (ADAR) mutagenic deaminases. In this analysis we apply what is known, or can reasonably be inferred, of the immunoglobulin somatic hypermutation (Ig SHM) mechanism to the analysis of the transcriptional stand asymmetries of the COSMIC SBS signatures that are observed in cancer genomes. The underlying assumption is that somatic mutations arising in cancer genomes are driven by dysregulated off-target Ig SHM-like mutagenic processes at non-Ig loci. It is reasoned that most SBS signatures whether of "unknown etiology" or assigned-molecular causation, can be readily understood in terms of the DRT-paradigm. These include the major age-related "clock-like" SBS5 signature observed in all cancer genomes sequenced and many other common subset signatures including SBS1, SBS3, SBS2/13, SBS6, SBS12, SBS16, SBS17a/17b, SBS19, SBS21, as well as signatures clearly arising from exogenous causation. We conclude that the DRT-model provides a plausible molecular framework that augments our current understanding of immunogenetic mechanisms driving oncogenesis. It accommodates both what is known about AID/APOBEC and ADAR somatic mutation strand asymmetries and provides a fully integrated understanding into the molecular origins of common COSMIC SBS signatures. The DRT-paradigm thus provides scientists and clinicians with additional molecular insights into the causal links between deaminase-associated genomic signatures and oncogenic processes.
本文对目前用于解释在《癌症体细胞突变目录》（COSMIC数据库，惠康桑格研究所）中整理的癌症基因组中观察到的单碱基替换（SBS）特征转录链不对称性的分子机制进行了批判性分析。该分析基于一种涉及胞嘧啶（AID/APOBEC）和腺苷（ADAR）诱变脱氨酶的癌症发生的脱氨酶驱动逆转录酶（DRT）诱变模型。在本分析中，我们将已知的或可以合理推断的免疫球蛋白体细胞超突变（Ig SHM）机制应用于对癌症基因组中观察到的COSMIC SBS特征转录链不对称性的分析。潜在假设是，癌症基因组中出现的体细胞突变是由非Ig基因座处失调的脱靶Ig SHM样诱变过程驱动的。据推测，大多数SBS特征，无论是“病因不明”的还是已确定分子病因的，都可以根据DRT范式轻松理解。这些包括在所有测序的癌症基因组中观察到的主要与年龄相关的“时钟样”SBS5特征以及许多其他常见的子集特征，包括SBS1、SBS3、SBS2/13、SBS6、SBS12、SBS16、SBS17a/17b、SBS19、SBS21，以及明显由外源性病因引起的特征。我们得出结论，DRT模型提供了一个合理的分子框架，增强了我们目前对驱动肿瘤发生的免疫遗传机制的理解。它既考虑了关于AID/APOBEC和ADAR体细胞突变链不对称性的已知信息，又对常见COSMIC SBS特征的分子起源提供了全面综合的理解。因此，DRT范式为科学家和临床医生提供了关于脱氨酶相关基因组特征与致癌过程之间因果联系的额外分子见解。
