Abstract

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

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Acknowledgements

We thank the patients who contributed samples to this study. This study was a collaboration of the Broad Institute in Cambridge, Massachusetts, USA, and the National Institute of Genomic Medicine (INMEGEN) in Mexico City, Mexico. The work was conducted as part of the Slim Initiative in Genomic Medicine for the Americas (SIGMA), a project funded by the Carlos Slim Foundation in Mexico. We are grateful to S. Romero-Cordoba, R. Rebollar, and L. Alfaro-Ruiz for sample collection and processing. We thank the Broad Institute Genomics Platform and Target Accelerator for assistance; N. Dyson for assistance with E2F experiments; A. Kamburov and D. Rosebrock for computational help; M. Snyder, J. Reuter, and C. Cenik for discussion on TBC1D12; and S. Nik-Zainal for data access guidance. E.R., M.R., A.T.W., C.S., M.C., and J.S.B. were partly funded by SIGMA. J.M.E. was supported by the Fannie and John Hertz Foundation. P.P. and A.B were partly funded by the Massachusetts General Hospital startup funds of G.G. G.G. was partly funded by the Paul C. Zamecnick, MD, Chair in Oncology at Massachusetts General Hospital.

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Affiliations

  1. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA

    • Esther Rheinbay
    • , Jonna Grimsby
    • , Grace Tiao
    • , Jesse M. Engreitz
    • , Jaegil Kim
    • , Michael S. Lawrence
    • , Amaro Taylor-Weiner
    • , Mara Rosenberg
    • , Julian Hess
    • , Chip Stewart
    • , Yosef E. Maruvka
    • , Petar Stojanov
    • , Maria L. Cortes
    • , Sara Seepo
    • , Carrie Cibulskis
    • , Adam Tracy
    • , Jesse S. Boehm
    • , Stacey B. Gabriel
    • , Matthew Meyerson
    • , Todd R. Golub
    • , Eric S. Lander
    •  & Gad Getz
  2. Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts 02129, USA

    • Esther Rheinbay
    • , Prasanna Parasuraman
    • , Michael S. Lawrence
    • , Yosef E. Maruvka
    • , Jesse Lee
    • , Zongli Zheng
    • , Leif W. Ellisen
    • , A. John Iafrate
    • , Toshi Shioda
    • , Andre Bernards
    •  & Gad Getz
  3. Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts 02139, USA

    • Jesse M. Engreitz
  4. Instituto de Enfermedades de la Mama FUCAM, A.C., Mexico City 04980, Mexico

    • Sergio Rodriguez-Cuevas
  5. Princess Margaret Cancer Centre, University Health Network and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada

    • Trevor J. Pugh
  6. Harvard Medical School, Boston, Massachusetts 02115, USA

    • Leif W. Ellisen
    • , Matthew Meyerson
    • , Todd R. Golub
    •  & Gad Getz
  7. Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Matthew Meyerson
    •  & Todd R. Golub
  8. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Jose Baselga
  9. Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico

    • Alfredo Hidalgo-Miranda
  10. Massachusetts General Hospital, Department of Pathology, Boston, Massachusetts 02114, USA

    • Gad Getz

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Contributions

G.G., M.M., T.R.G., and E.S.L. conceived and designed the study. A.H.-M., S.R.-C., J.B., and L.W.E. contributed patient samples. E.R. and G.G. designed analysis and developed methods. E.R., J.K., G.T., A.T.-W., and P.S. performed data analysis. P.P., J.G., J.M.E., T.S., Z.Z., J.L., and E.R. performed experiments. M.S.L., J.H., M.R., T.J.P., Y.E.M., and C.S. contributed data and analysis tools. M.L.C., S.S., C.C., and A.T. provided project management. G.G., S.B.G., J.S.B., M.M., A.J.I., A.B., T.R.G., and E.S.L. provided project leadership. E.R., E.S.L., and G.G. wrote the manuscript.

Competing interests

Competing financial interests: A.J.I. holds equity in and receives royalties from ArcherDx.

Corresponding author

Correspondence to Gad Getz.

Reviewer Information Nature thanks J. Carroll and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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https://doi.org/10.1038/nature22992

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