Table 1.

Examples of exogenous mutagens and endogenous mutagenic processes

Mutagen	Dominant mutations*	Extended context*	Studies reporting mutation signatures	Prevalence	Challenges
Exogenous
Aristolochic acid	A > T	(C|T)AG > (C|T)TG	[16-19]	Widely used in traditional medicines [20]; exposure to AA is widespread in Taiwan [17]	No unusual challenges
UV radiation	C > T; strand bias; CC > TT	TC > TT (C|T)C > (C|T)T	[6,8,9,21-23]	Prevalence of signature: 87% of melanoma [8]	No unusual challenges
Tobacco smoke	Primarily C > A, some C > G and C > T	CG > AG CG > TG; CG > GG	[8,14,24-26]	Extensive epidemiological evidence of the role of tobacco smoke in cancer [27,28]	Contains multiple carcinogens with individually unknown signatures
Aflatoxin B1	Primary G > T;some G > A	NA	[29-34]	[29,35]	Signature in extended context not known
Temozolomide	C > T	CC > TC; CT > TT	[8,36,37]	Present in 10% of glioblastomas; 9% of melanoma [8]	No unusual challenges
Benzene	C > T; C > A	NA	[38]	Exposure associated with risk of leukemia [39,40]	Several mutagenic metabolites and signature in extended context not known
Endogenous
Activated APOBEC	C > T	TCA > TTA	[8,41,42]	Present in 16 tumor types [8]	Signatures 2 and 13 are similar [8], except 2 has C > T and 13 has higher C > G
Mutated DNA polymerase epsilon	C > T	TCG > TTG; TCT > TAT	[8,13]	Present in 13.7% of uterus cancer and 36.7% of colorectal cancer [8]	No unusual challenges
Mismatch repair deficiency (MSI)	C > T; C > A	CG > TG; CT > AT; homopolymer and microsatellite length changes	[8]	Present in 9 tumor types [8]	No unusual challenges
Correlated with patient age	C > T	CG > TG	[8]	A majority of tumors of most types have this signature [8]	Interpretation of two similar signatures in [8] not clear

*The ' > ' symbol indicates a change from one nucleotide to another; a vertical line indicates alternative nucleotides. NA, not applicable.