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We are grateful to L. Pasqualucci, who provided the pCMV-HA-
KMT2D and the corresponding mutants, the N5437S and R5432W
KMT2D plasmids. We also thank A. Shilatifard, who provided the
KMT2D antibody for our preliminary experiments; P. Giresi,
A. Krivtsov, and Y. Li for help with ATAC-seq; Y. Zou for help
with ChIP-seq; N. Morse for help with xenograft establishment;
and N. Socci for help with microarray analysis. This work was
supported by NIH grant RO1CA190642-01A1, the Breast Cancer
Research Foundation, and the Geoffrey Beene Cancer Research
Center (to J.B.); National Cancer Institute (NCI) Cancer Center
Support Grant P30CA08748 to the Microchemistry and Proteomics
Core Laboratory of the Memorial Sloan Kettering Cancer Center;
and NIH grants CA66996 and CA140575 to S.A.A. We are also
grateful for the support of T. and B. Weinstein. E. T. holds a
fellowship from the Terri Brodeur Breast Cancer Foundation.
H.U.O. is supported by NCI award K99 CA207871. J.B. and M.N.D.
are paid consultants for Novartis Pharmaceuticals. S.A.A. is
a paid consultant for Epizyme, Imago Biosciences, and Vitae
Pharmaceuticals. Memorial Sloan Kettering Cancer Center and
the authors (E. T., S.A.A., and J.B.) have filed a patent application
(U.S. patent registration number 62/420324) related to KMT2D
inhibition as a treatment for breast cancer. The sequencing
data have been deposited in the Gene Expression Omnibus database
under accession numbers GEO GSE84515, GSE84593, GSE84594,
Materials and Methods
Figs. S1 to S8
Tables S1 to S3
2 August 2016; resubmitted 23 December 2016
Accepted 27 February 2017
Stem cell divisions, somatic
mutations, cancer etiology, and
Cristian Tomasetti,1,2 Lu Li,2 Bert Vogelstein3*
Cancers are caused by mutations that may be inherited, induced by environmental
factors, or result from DNA replication errors (R). We studied the relationship between
the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries
throughout the world. The data revealed a strong correlation (median = 0.80) between
cancer incidence and normal stem cell divisions in all countries, regardless of their
environment. The major role of R mutations in cancer etiology was supported by an
independent approach, based solely on cancer genome sequencing and epidemiological
data, which suggested that R mutations are responsible for two-thirds of the mutations
in human cancers. All of these results are consistent with epidemiological estimates of the
fraction of cancers that can be prevented by changes in the environment. Moreover, they
accentuate the importance of early detection and intervention to reduce deaths from the
many cancers arising from unavoidable R mutations.
It is now widely accepted that cancer is the result of the gradual accumulation of driver gene mutations that successively increase cell proliferation (1–3). But what causes these muta- tions? The role of environmental factors (E)
in cancer development has long been evident
from epidemiological studies, and this has fun-
damental implications for primary prevention.
The role of heredity (H) has been conclusively
demonstrated from both twin studies (4) and the
identification of the genes responsible for cancer
predisposition syndromes (3, 5). We recently hy-
pothesized that a third source—mutations due to
the random mistakes made during normal DNA
replication (R)—can explain why cancers occur
much more commonly in some tissues than others
(6). This hypothesis was based on our observation
that, in the United States, the lifetime risks of
cancer among 25 different tissues were strongly
correlated with the total number of divisions of
the normal stem cells in those tissues (6, 7). It has
1330 24 MARCH 2017 • VOL 355 ISSUE 6331
1Division of Biostatistics and Bioinformatics, Department of
Oncology, Sidney Kimmel Cancer Center, Johns Hopkins
University School of Medicine, 550 North Broadway,
Baltimore, MD 21205, USA. 2Department of Biostatistics,
Johns Hopkins Bloomberg School of Public Health, 615 North
Wolfe Street, Baltimore, MD 21205, USA. 3Ludwig Center and
Howard Hughes Medical Institute, Johns Hopkins Kimmel
Cancer Center, 1650 Orleans Street, Baltimore, MD 21205, USA.
*Corresponding author. Email: firstname.lastname@example.org (C. T.);
Fig. 1. Correlations between
stem cell divisions and cancer
incidence in different countries. For each country, the
correlation between the number
of stem cell divisions in 17 different tissues and the lifetime incidence of cancer in those tissues
was calculated. This resulted in
correlation coefficients, which
were grouped and plotted into a
histogram. In this histogram, the
x axis represents the correlation
coefficients and the y axis represents the number of countries
with the corresponding correlation coefficient. For example,
there were seven countries in
which the correlation between
the number of stem cell divisions
and cancer incidence was between 0.82 and 0.83; these seven countries are represented by the tallest
green bar in the histogram. The median correlation coefficient over all countries was 0.8. The black
line represents the density for the observed distribution of the correlation coefficient among different