Robyn A. Lindley

Somatic mutation patterns in non-lymphoid cancers resemble the strand biased somatic hypermutation spectra of antibody genes

It has been long accepted that many types of B cell cancer (lymphomas, myelomas, plasmacytomas, etc.) are derived from the antigen-stimulated B cell Germinal Center (GC) reaction [1], [2], [3] and [4], i.e. they are aberrant products of the somatic hypermutation mechanism normally targeting rearranged immunoglobulin (Ig) variable genes (so-called V[D]J regions). Here we provide evidence that the somatic mutation patterns of some well-characterised cancer genomes [5] such as lung carcinomas, breast carcinomas and squamous cell carcinomas, strongly resemble in toto or in part the spectrum of somatic point mutations observed in normal physiological somatic hypermutation (SHM) in antibody variable genes [6]. This implies that whilst SHM itself is a tightly regulated and beneficial mutational process for B lymphocytes of the immune system, aberrant mutations (or “crises”) or inadvertent activation of this complex activation-induced cytidine deaminase (AID)-dependent mechanism in a range of somatic tissue types could result, as often speculated [7], in cancer.

Critical Analysis of Strand-Biased Somatic Mutation Signatures in TP53 versus Ig Genes, in Genome-Wide Data and the Etiology of Cancer

Previous analyses of rearranged immunoglobulin (Ig) variable genes (VDJs) concluded that the mechanism of Ig somatic hypermutation (SHM) involves the Ig pre-mRNA acting as a copying template resulting in characteristic strand biased somatic mutation patterns at A:T and G:C base pairs. We have since analysed cancer genome data and found the same mutation strand-biases, in toto or in part, in nonlymphoid cancers. Here we have analysed somatic mutations in a single well-characterised gene TP53. Our goal is to understand the genesis of the strand-biased mutation patterns in TP53—and in genome-wide data—that may arise by “endogenous” mechanisms as opposed to adduct-generated DNA-targeted strand-biased mutations caused by well-characterised “external” carcinogenic influences in cigarette smoke, UV-light, and certain dietary components. The underlying strand-biased mutation signatures in TP53, for many non-lymphoid cancers, bear a striking resemblance to the Ig SHM pattern. A similar pattern can be found in genome-wide somatic mutations in cancer genomes that have also mutated TP53. The analysis implies a role for base-modified RNA template intermediates coupled to reverse transcription in the genesis of many cancers. Thus Ig SHM may be inappropriately activated in many non-lymphoid tissues via hormonal and/or inflammation-related processes leading to cancer.

Association between targeted somatic mutation (TSM) signatures and HGS‐OvCa progression

Evidence already exists that the activation‐induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence (“motif”) surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis. If successful, a secondary objective is to investigate if such changes are associated with disease progression indicators that include disease stage and progression‐free survival time. Using a discovery cohort of 194 high‐grade serous ovarian adenocarcinoma (HGS‐OvCa) exomes, the results confirm the ability of the novel in silico approach used to identify changes in the preferred target motifs for AID, APOBEC3G, APOBEC3B, and ADAR1 during oncogenesis. Using this approach, a set of new cancer‐progression associated signatures (C‐PASs) were identified. Furthermore, it was found that the C‐PAS identified can be used to differentiate between the cohort of patients that remained progression‐free for longer than 60 months, from those in which disease progressed within 60 months (sensitivity 95%, specificity 90%). The spectrum of outcomes observed here could provide a foundation for future clinical assessment of susceptibility variants in ovarian, and several other cancers as disease progresses. The ability of the in silico methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis.

APOBEC and ADAR deaminases may cause many single nucleotide polymorphisms curated in the OMIM database

Cytosine and adenosine deamination events (DNA, RNA substrates) account for most codon-context Targeted Somatic Mutation (TSM) patterns observed in immunoglobulin (Ig) somatic hypermutation (SHM), and in cancer exomes following Ig-SHM-like responses. TSM refers to the process of somatic mutagenesis involving deamination events that results on a dominant type of mutation (e.g., C-to-T), and co-incident at a particular motif (e.g., WRC), and preferentially targeting the first, second or third nucleotide position within the mutated codon (e.g. MC1, MC2 or MC3, read 5-prime to 3-prime). It is now widely accepted that if left uncorrected, the accumulation of uncorrected TSMs involving the deaminases, may lead to a diagnosis of cancer or other degenerative disease. Our hypothesis is that many missense, nonsense and synonymous single nucleotide polymorphisms (SNPs) associated with clinically significant diseases may have arisen in the population by similar highly targeted deamination events. The OMIM database was searched for disease-associated SNPs on the X chromosome, and for all chromosomes. The nucleotide substitution patterns for disease-associated SNPs were analyzed by the TSM method to identify the likely deaminase source for C-to-U (C-to-T/G-to-A) and A-to-I (A-to-G/T-to-C) derived gene mutations preferentially targeting known sequence motifs associated with the deaminases: AID, APOBEC3G, APOBEC3B and ADAR 1/2. Of the 789 OMIM SNPs analysed. In both data sets, the mutation targeting preferences within the mutated codon reveal a statistically significant bias (p < 0.001). The results imply that a deamination of C-site and A-site targets are written into the human germline for the chromosome wide exomic SNPs analysed. This is consistent with previously observed mutation patterns arising in cancer genomes and hypermutated Ig genes during SHM. The results imply that similar types of deaminase-mediated molecular processes that occur in somatic hypermutation and cancer, may be contributing causative drivers of human exomic SNPs.