APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

Butler, Kelly; Banday, A. Rouf

doi:10.1186/s13045-023-01425-5

Journal of Hematology & Oncology

Table 2 Germline variants affecting APOBEC3s and cancer risk

From: APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

Germline variant	Genomic location	Risk allele or amino acid	Cancer	Molecular impact*	Effect on cancer risk*	References
rs139293	Exon 2 of APOBEC3H	T	Lung	Activity-decreasing amino acid change (R18L) and lower expression of APOBEC3H and APOBEC3C	Decreased	[107]
rs1014971 Linked proxies: rs17000526 rs1004748	Intergenic region ~ 25 kb from APOBEC3A	T	Bladder	Increased APOBEC3B expression and more APOBEC3-induced mutations	Increased	[61]
				N/A	Increased	[63]
				N/A	Increased overall and for high-risk tumors	[103]
			Breast	Increased APOBEC3B expression but no association with APOBEC3-induced mutation burden	Moderately increased	[61]
rs2267401	APOBEC3B promoter	G	Bile duct	Increased APOBEC3B promoter activity	Increased	[43]
			Liver	Increased APOBEC3B expression with stronger promoter response to IL-6 and more APOBEC3-induced HBV mutations	Increased	[86]
			Gallbladder	Decreased APOBEC3B promoter activity	Decreased	[43]
rs12157810	APOBEC3A promoter	C	Bile duct	Increased APOBEC3A promoter activity	Decreased	[43]
			Gallbladder	Increased APOBEC3A promoter activity	Decreased	[43]
			Renal	Higher APOBEC3A expression and increased promoter sensitivity to TNF-α	Decreased	[108]
			Colorectal	No change in promoter responsiveness to TNF-α, but decreased response to IL-6	N/A	[108]
APOBEC3H Haplotype I	APOBEC3H		Lung	Gly105 creates unstable APOBEC3H protein with increased nuclear localization	Increased	[65]
rs34522862	Exon 2	Asn
rs139293	Exon 2	Arg
rs139297	Exon 3	Gly
rs139299	Exon 3	Lys
re139298	Exon 3	Lys
rs139302	Exon 4	Glu
rs139298	APOBEC3H Exon 3	Glu	Lung	K121E within APOBEC3H haplotype I destabilizes protein, potentially creating fewer mutations to avoid immune response	Decreased relative to standard haplotype I	[106]
APOBEC3A/B chimera Proxy: rs12628403	Coding region of APOBEC3B	~ 30 kb deletion	Breast	Enrichment of APOBEC3-induced mutations	Increased	[61]
				Increased APOBEC3-induced mutation load	N/A	[62]
				Higher abundance of tumor-infiltrating immune cells	Increased	[109]
				N/A	Increased for higher histological grade	[64]
				Hypermutated phenotype with immune activation	N/A	[105]
			Leukemia	Hypermutated tumor genome	N/A	[62]
			Ovarian	N/A	Decreased	[110]
			Bladder	No association	No association	[61]
APOBEC3B indel	Exon 5 of APOBEC3B	Deletion	Breast	N/A	Increased	[111]

^*N/A indicates that the study did not test for molecular impact or clinical association

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ISSN: 1756-8722

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