Echoed induction of nucleotide variants and chromosomal structural variants in cancer cells

Abstract

Generally, the number of single-nucleotide variants (SNVs) in somatic cells increases with age, which is expected for replication errors. The number of SNVs in cancer cells, however, is often much higher than that in somatic cells, raising the question of whether cancer cells possess SNV induction pathways. The present study shows that the number of SNVs in cancer cells correlates with the number of chromosomal structural variants (SVs). While Kataegis, localized hypermutations typically arising near SV sites, revealed multiple SNVs within 1 kb, SV-associated SNVs were generally observed within 0.1–1 Mb of SV sites, irrespective of Kataegis status. SNVs enriched within 1 Mb of SV regions were associated with deficiency of DNA damage repair, including HR deficiency-associated single base substitution 3 (SBS3) and exogenous damage-associated SBS7 and SBS36 signatures. We also observed a similar correlation between SVs and SNVs in cells that had undergone clonal evolution in association with genomic instability, implying an association between genomic instability and SV-associated induction of SNVs.

Single base substitution signatures 17a, 17b, and 40 are induced by γ-ray irradiation in association with increased reactive oxidative species

“…SVs including chromosomal translocations are induced by erroneous DSB repair between unpaired chromosomal ends, whereas SNVs are induced by DNA polymerase errors during DNA replication [ 9 ]. Although SVs and SNVs are induced by distinct pathways, their inductions are tightly associated with genomic instability, which can lead to clonal evolution of aberrant clones, as shown in the MEF model [ [10] , [11] , [12] ]. Even in the human genome, while SNVs in normal organs generally increase with age [ [13] , [14] , [15] ] as a consequence of DNA replication errors [ 16 , 17 ], those in the cancer genome are more tightly associated with SVs [ 10 ], implying that SNVs in cancer cells are often induced in association with genomic instability.…”

“…Although SVs and SNVs are induced by distinct pathways, their inductions are tightly associated with genomic instability, which can lead to clonal evolution of aberrant clones, as shown in the MEF model [ [10] , [11] , [12] ]. Even in the human genome, while SNVs in normal organs generally increase with age [ [13] , [14] , [15] ] as a consequence of DNA replication errors [ 16 , 17 ], those in the cancer genome are more tightly associated with SVs [ 10 ], implying that SNVs in cancer cells are often induced in association with genomic instability. Supporting this argument, the SBS signatures associated with genomic instability, such as homologous recombination (HR) deficiency-associated SBS3 and DNA damage-associated SBS18, accumulate to high levels, especially around SV sites (<1 M base) [ 10 ].…”

“…Even in the human genome, while SNVs in normal organs generally increase with age [ [13] , [14] , [15] ] as a consequence of DNA replication errors [ 16 , 17 ], those in the cancer genome are more tightly associated with SVs [ 10 ], implying that SNVs in cancer cells are often induced in association with genomic instability. Supporting this argument, the SBS signatures associated with genomic instability, such as homologous recombination (HR) deficiency-associated SBS3 and DNA damage-associated SBS18, accumulate to high levels, especially around SV sites (<1 M base) [ 10 ]. SBS signature types could be altered by the environmental background, e.g., inflammation, which leads to deamination-associated signatures SBS2 and SBS13.…”

Disentangling sources of clock-like mutations in germline and soma

“…The number of mutations attributed to SBS1 correlates with the age of cancer diagnosis in many cancer types, as do mutations assigned to SBS5, leading the two signatures to be described as “clocklike” [13]. Because they share this behavior, mutations attributed to these two signatures are sometimes combined and analyzed together [14–16].…”

“…leading the two signatures to be described as "clocklike" [13]. Because they share this behavior, mutations attributed to these two signatures are sometimes combined and analyzed together [14][15][16].…”