The Repertoire of Mutational Signatures in Human Cancer

Cancer is the most common human genetic disease. All cancers are caused by
somatic mutations. These mutations may be the consequence of the intrinsic slight
infidelity of the DNA replication machinery, exogenous or endogenous mutagen
exposures, enzymatic modification of DNA, or defective DNA repair. In some cancer
types, a substantial proportion of somatic mutations are known to be generated by
exogenous carcinogens, for example, tobacco smoking in lung cancers and
ultraviolet light in skin cancers, or by abnormalities of DNA maintenance, for
example, defective DNA mismatch repair in some colorectal cancers.
Each biological process causing mutations leaves a characteristic imprint on the
genome of a cancer cell, termed, mutational signature. In this talk, I will present
mutational signatures analyses encompassing 23,517 cancer genomes across 40
distinct types of human cancer revealing more than 60 different signatures of
mutational processes. Some signatures are present in many cancer types, notably a
signature attributed to the APOBEC family of cytidine deaminases, whereas others
are confined to a single cancer class. Certain signatures are associated with age of
the patient at cancer diagnosis, known mutagenic exposures or defects in DNA
maintenance, but many are of cryptic origin. The results reveal the diversity of
mutational processes underlying the development of cancer, with potential
implications for understanding of cancer etiology, prevention and therapy.