title: Age-related somatic mutations in the cancer genome.
abstract: Aging is associated with an increased risk of cancer, possibly in part because of an age-related increase in mutations in normal tissues. Due to their extremely low abundance, somatic mutations in normal tissues frequently escape detection. Tumors, as clonal expansions of single cells, can provide information about the somatic mutations present in these cells prior to tumorigenesis. Here, we used data from The Cancer Genome Atlas (TCGA), to systematically study the frequency and spectrum of somatic mutations in a total of 6,969 patients and 34 different tumor types as a function of the age of the patient. After using linear modeling to control for the age structure of different tumor types, we found that the number of identified somatic mutations increases exponentially with age. Using additional data from the literature, we found that accumulation of somatic mutations is associated with cell division rate, cancer risk and cigarette smoking, with the latter also associated with a distinct spectrum of mutations. Our results confirm that aging is associated with the accumulation of somatic mutations, and strongly suggest that the level of genome instability of normal cells, modified by both endogenous and environmental factors, is the main risk factor for cancer.
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Milholland
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Auton
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D016922:Cellular Senescence; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: aging; bioinformatics; genomics; sequencing; somatic mutation