Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 7;15(3):e1006881.
doi: 10.1371/journal.pcbi.1006881. eCollection 2019 Mar.

Estimating the number of genetic mutations (hits) required for carcinogenesis based on the distribution of somatic mutations

Ramu Anandakrishnan  1   2 , Robin T Varghese  1   2 , Nicholas A Kinney  1   2 , Harold R Garner  1   2
Affiliations

Estimating the number of genetic mutations (hits) required for carcinogenesis based on the distribution of somatic mutations

Ramu Anandakrishnan et al. PLoS Comput Biol. .

Abstract

Individual instances of cancer are primarily a result of a combination of a small number of genetic mutations (hits). Knowing the number of such mutations is a prerequisite for identifying specific combinations of carcinogenic mutations and understanding the etiology of cancer. We present a mathematical model for estimating the number of hits based on the distribution of somatic mutations. The model is fundamentally different from previous approaches, which are based on cancer incidence by age. Our somatic mutation based model is likely to be more robust than age-based models since it does not require knowing or accounting for the highly variable mutation rate, which can vary by over three orders of magnitude. In fact, we find that the number of somatic mutations at diagnosis is weakly correlated with age at cancer diagnosis, most likely due to the extreme variability in mutation rates between individuals. Comparing the distribution of somatic mutations predicted by our model to the actual distribution from 6904 tumor samples we estimate the number of hits required for carcinogenesis for 17 cancer types. We find that different cancer types exhibit distinct somatic mutational profiles corresponding to different numbers of hits. Why might different cancer types require different numbers of hits for carcinogenesis? The answer may provide insight into the unique etiology of different cancer types.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Illustration of the multi-hit model.
A short genome with three (k = 3) possible 2-hit (h = 2) combinations of carcinogenic mutations. The 2-hit combinations are shown with yellow/green/purple shaded background. Somatic mutations are outlined in red. One (purple) of the three combinations occurs with five (m = 5) somatic mutations, resulting in carcinogenesis.
Fig 2
Fig 2. Somatic mutations at diagnosis are weakly correlated with age at cancer diagnosis.
Pearson’s linear correlation between somatic mutations and age at diagnosis ranges from -0.2 to +0.2, except for kidney chromophobe for which there were only nine matched tumor and blood derived normal samples.
Fig 3
Fig 3. Number of hits estimated by the multi-combination multi-hit model depends on the distribution of somatic mutations.
(a)-(c) Examples of three cancer types exhibiting distinct distributions and the predicted probability distribution for the optimal model, showing a corresponding difference in the number of hits. S1–S3 Figs show the distributions for the 17 cancer types with at least 200 samples.
Fig 4
Fig 4. Graphical summary of estimated number of hits by cancer type.
Derived from the public domain image by M Haggstrom (2014).
Fig 5
Fig 5. Estimated number of hits are moderately correlated to lifetime stem cell division.
Pearson’s linear coefficient = 0.522, suggesting that number of hits may depend on cellular growth characteristics of individual tissues. However, the 95% confidence interval = -0.29–0.90, indicating that the relationship may be coincidental. Estimates for lifetime stem cell divisions were from S1 Table of Ref. (29).
Fig 6
Fig 6. Distribution of somatic mutations for breast invasive carcinoma (BRCA) is similar by subtype and stage.
The estimated number of hits is identical for subsets of BRCA samples by (a) subtype and (b) stage.
See this image and copyright information in PMC

References

    1. Ciriello G, Miller M, Aksoy B, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nature Genetics. 2013;45(10):1127–33. 10.1038/ng.2762 - DOI - PMC - PubMed
    1. Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646–74. 10.1016/j.cell.2011.02.013 - DOI - PubMed
    1. Futreal A, Coin L, Marshall M, Down T, Hubbard T, Wooster R, et al. A census of human cancer genes. Nat Rev Cancer. 2004;4(3):177–83. 10.1038/nrc1299 - DOI - PMC - PubMed
    1. Tomasetti C, Marchionni L, Nowak M, Parmigiani G, Vogelstein B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A. 2015;112(1):118–23. 10.1073/pnas.1421839112 - DOI - PMC - PubMed
    1. Zhang X, Simon R. Estimating the number of rate limiting genomic changes for human breast cancer. Breast Cancer Res Treat. 2005;91(2):121–4. 10.1007/s10549-004-5782-y . - DOI - PubMed

Publication types