Age-related somatic mutations in the cancer genome.

Brandon Milholland,Adam Auton,Yousin Suh,Jan Vijg

doi:10.18632/oncotarget.5685

Brandon Milholland, Adam Auton + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.5685

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Journal: Oncotarget	Publication Date: Sep 17, 2015
Citations: 119	License type: cc-by

Affiliation: Albert Einstein College of Medicine

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.

Highlights

Somatic mutations are generally accepted to cause cancer and have been implicated as a cause of aging [1]
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 associated with a distinct spectrum of mutations
We used the extensive amount of cancer genomic data available in The Cancer Genome Atlas (TCGA) to demonstrate a large and life-long increase in somatic mutation frequency across many tumor types

Summary

Introduction

Somatic mutations are generally accepted to cause cancer and have been implicated as a cause of aging [1]. Reporter genes may not always be representative of the genome overall, and with the emergence of next-generation sequencing it has become feasible to inexpensively characterize genome-wide, age-related mutation frequencies and spectra directly in different organs and tissues. A considerable fraction of all mutations in a tumor may reflect the frequency and spectrum of somatic mutations in normal human cells as these accumulated with age [5]. Recent massive cancer-sequencing efforts, such as The Cancer Genome Atlas (TCGA), have made available a wealth of data on tumor-associated somatic mutations from many individuals and tissue types [7,8,9]

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