TY - JOUR

T1 - Mutational signatures and mutable motifs in cancer genomes

AU - Rogozin, Igor B.

AU - Pavlov, Youri I.

AU - Goncearenco, Alexander

AU - De, Subhajyoti

AU - Lada, Artem G.

AU - Poliakov, Eugenia

AU - Panchenko, Anna R.

AU - Cooper, David N.

N1 - Funding Information: The Intramural Research Program of the National Library of Medicine at the National Institutes of Health (to I.B.R., A.G. and A.R.P.); the National Institutes of Health Intramural Research Program of the National Eye Institute (to E.P.); Boettcher Foundation, American Cancer Society, P30 CA072720 (to S.D.); Nebraska Department of Health and Human Services LB506, grant 2017-48 (to Y.I.P.); and Qiagen Inc through a License Agreement with Cardiff University (to D.N.C.)

PY - 2017/5/30

Y1 - 2017/5/30

N2 - Cancer is a genetic disorder, meaning that a plethora of different mutations, whether somatic or germ line, underlie the etiology of the 'Emperor of Maladies'. Point mutations, chromosomal rearrangements and copy number changes, whether they have occurred spontaneously in predisposed individuals or have been induced by intrinsic or extrinsic (environmental) mutagens, lead to the activation of oncogenes and inactivation of tumor suppressor genes, thereby promoting malignancy. This scenario has now been recognized and experimentally confirmed in a wide range of different contexts. Over the past decade, a surge in available sequencing technologies has allowed the sequencing of whole genomes from liquid malignancies and solid tumors belonging to different types and stages of cancer, giving birth to the new field of cancer genomics. One of the most striking discoveries has been that cancer genomes are highly enriched with mutations of specific kinds. It has been suggested that these mutations can be classified into 'families' based on their mutational signatures. A mutational signature may be regarded as a type of base substitution (e.g. C:G to T:A) within a particular context of neighboring nucleotide sequence (the bases upstream and/or downstream of the mutation). These mutational signatures, supplemented by mutable motifs (a wider mutational context), promise to help us to understand the nature of the mutational processes that operate during tumor evolution because they represent the footprints of interactions between DNA, mutagens and the enzymes of the repair/replication/modification pathways.

AB - Cancer is a genetic disorder, meaning that a plethora of different mutations, whether somatic or germ line, underlie the etiology of the 'Emperor of Maladies'. Point mutations, chromosomal rearrangements and copy number changes, whether they have occurred spontaneously in predisposed individuals or have been induced by intrinsic or extrinsic (environmental) mutagens, lead to the activation of oncogenes and inactivation of tumor suppressor genes, thereby promoting malignancy. This scenario has now been recognized and experimentally confirmed in a wide range of different contexts. Over the past decade, a surge in available sequencing technologies has allowed the sequencing of whole genomes from liquid malignancies and solid tumors belonging to different types and stages of cancer, giving birth to the new field of cancer genomics. One of the most striking discoveries has been that cancer genomes are highly enriched with mutations of specific kinds. It has been suggested that these mutations can be classified into 'families' based on their mutational signatures. A mutational signature may be regarded as a type of base substitution (e.g. C:G to T:A) within a particular context of neighboring nucleotide sequence (the bases upstream and/or downstream of the mutation). These mutational signatures, supplemented by mutable motifs (a wider mutational context), promise to help us to understand the nature of the mutational processes that operate during tumor evolution because they represent the footprints of interactions between DNA, mutagens and the enzymes of the repair/replication/modification pathways.

KW - Cancer genomics

KW - Classification

KW - DNA sequence context

KW - Methylation

KW - Mutation spectra

KW - Somatic hypermutation

KW - Gene Expression

KW - Genetic Predisposition to Disease

KW - Genomics

KW - Humans

KW - Selection, Genetic

KW - Mutagens/pharmacology

KW - Neoplasms/genetics

KW - DNA/genetics

KW - DNA Methylation

KW - Models, Genetic

KW - Mutation

KW - Oncogenes

KW - Evolution, Molecular

UR - http://www.scopus.com/inward/record.url?scp=85057550637&partnerID=8YFLogxK

U2 - 10.1093/bib/bbx049

DO - 10.1093/bib/bbx049

M3 - Article

C2 - 28498882

AN - SCOPUS:85057550637

VL - 19

SP - 1085

EP - 1101

JO - Briefings in Bioinformatics

JF - Briefings in Bioinformatics

SN - 1467-5463

IS - 6

ER -