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

Table 4

Effect of main DNA repair deficiencies in Ig somatic hypermutation studies in mice.

Gene-protein deficiency^†	Effect on frequency of		References
	A/T mutations	G/C mutations
UNG−/−	15% suppression; (A≫T strand bias)	95% C-to-T/G-to-A	[10]
UNG−/−MSH2−/−	98% suppression	>99.5% C-to-T/G-to-A; (C≫G 1.5x 𝑃<0.001)	[11]; See [3]
Pol𝜂 −/−	70% suppression; (residual A≫T)	No change (enriched in expected proportion)	[12]^†; [13]
Pol𝜅−/−	No change	No change	[14]
Pol𝜄−/−	No change	No change	[15]
Pol𝜂 −/−Pol𝜅−/−	87% suppression; (residual A≫T)	No change (enriched in expected proportion)	[16]
MSH2−/−	80% suppression; (residual A≫T ?)	>80% C-to-T/G-to-A; (C≫G 1.5x 𝑃<0.05)	[13]
Pol𝜂−/−MSH2−/−	>99% suppression	>85% C-to-T/G-to-A; (C≫G 1.5x 𝑃<0.001)	[13]
Ogg1(−/−)^§	No change	No change	[9]
Aag(−/−)^¶	No effect on A-to-G mutation frequency. Slight statistically significant increase in T-to-C and thus slight reduction in A≫T strand bias.	No change	[17]
p53(−/−)	56% increase in A-to-G; (increased A≫T strand bias)	Decreased G-to-A.; Enhanced G-to-C versus C-to-G ratio and thus strand bias.	[18]

†All experimental mouse studies except work in cells from human Xeroderma Pigmentosium Variant (XPV) patients with genetic deficiency in DNA polymerase 𝜂 (eta), Zeng et al. [12]. UNG, uracil DNA glycosylase, removes uracil from DNA generating an abasic site; MSH2, MSH2 protein component of MSH2-MSH6 mismatch repair heterodimer; Pol𝜂, DNA polymerase eta, Y family polymerase; Pol𝜅, DNA polymerase kappa, Y family polymerase; Pol𝜄, DNA polymerase iota, Y family polymerase; “−/−”, homozygous deficiency (gene knock-out mouse line); ^¶Aag, alkyladenine DNA glycosylase which removes hypoxanthine (deaminated adenine) from DNA generating an abasic site; ^§Ogg1, 8-hydroxyguanine-DNA glycosylase which removes oxidised guanine (“8oxoG”) from DNA thus generating an abasic site. Not shown are two additional deficiencies. (a) The effect of Rev1 deficiency which affects G-to-C mutations as Rev1 plays a special and limited role in SHM by inserting dC opposite dU and abasic sites in VDJ DNA carrying AID-induced lesions, Jansen et al. [19] and Steele [3] (member of Y family polymerase family); and (b) the effect of DNA polymerases zeta (ξ) deficiency where studies show Pol-𝜉 plays a special role in SHM by generating the observed low frequency tandem mutations in immunoglobulin variable regions, Saribasak et al. [20]. C≫G. mutations off C exceed mutations off G by ratio indicated; A≫T, mutations off A exceed mutations off T by ratio indicated.