Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Somatic mutation of CDKN1B in small intestine neuroendocrine tumors

Abstract

The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mutational analysis of 31 primary and 19 metastatic SI-NETs.
Figure 2: Somatic mutation and copy number discordance between primary and metastatic tumors.

Similar content being viewed by others

References

  1. Vinik, A.I. et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas 39, 713–734 (2010).

    Article  PubMed  Google Scholar 

  2. Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kulke, M.H. et al. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosom. Cancer 47, 591–603 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Cunningham, J.L. et al. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes Chromosom. Cancer 50, 82–94 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Banck, M.S. et al. The genomic landscape of small intestine neuroendocrine tumors. J. Clin. Invest. 123, 2502–2508 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Getz, G. et al. Comment on “The consensus coding sequences of human breast and colorectal cancers”. Science 317, 1500 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Hatta, Y., Takeuchi, S., Yokota, J. & Koeffler, H.P. Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3–13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes. Br. J. Cancer 75, 1256–1262 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kibel, A.S., Freije, D., Isaacs, W.B. & Bova, G.S. Deletion mapping at 12p12–13 in metastatic prostate cancer. Genes Chromosom. Cancer 25, 270–276 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Takeuchi, S. et al. Frequent loss of heterozygosity in region of the KIP1 locus in non-small cell lung cancer: evidence for a new tumor suppressor gene on the short arm of chromosome 12. Cancer Res. 56, 738–740 (1996).

    CAS  PubMed  Google Scholar 

  13. Pietenpol, J.A. et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Res. 55, 1206–1210 (1995).

    CAS  PubMed  Google Scholar 

  14. Hetet, G. et al. Recurrent molecular deletion of the 12p13 region, centromeric to ETV6/TEL, in T-cell prolymphocytic leukemia. Hematol. J. 1, 42–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Le Toriellec, E. et al. Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia. Blood 111, 2321–2328 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Barbieri, C.E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Muraoka, R.S. et al. ErbB2/Neu-induced, cyclin D1–dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. Mol. Cell Biol. 22, 2204–2219 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gao, H. et al. A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis. Proc. Natl. Acad. Sci. USA 101, 17204–17209 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sancho, R. et al. F-box and WD repeat domain–containing 7 regulates intestinal cell lineage commitment and is a haploinsufficient tumor suppressor. Gastroenterology 139, 929–941 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Ying, H. et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB–cytokine network. Cancer Discov. 1, 158–169 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumar, M.S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23, 2700–2704 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zimmer, S.N. et al. Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. Blood 118, 69–79 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721–732 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Nakayama, K. et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Fero, M.L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85, 733–744 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Fero, M.L., Randel, E., Gurley, K.E., Roberts, J.M. & Kemp, C.J. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396, 177–180 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  28. Solimini, N.L. et al. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 337, 104–109 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rudin, C.M. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 44, 1111–1116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Habbe, N., Fendrich, V., Heverhagen, A., Ramaswamy, A. & Bartsch, D.K. Outcome of surgery for ileojejunal neuroendocrine tumors. Surg. Today 43, 1168–1174 (2013).

    Article  PubMed  Google Scholar 

  35. Polish, A., Vergo, M.T. & Agulnik, M. Management of neuroendocrine tumors of unknown origin. J. Natl. Compr. Canc. Netw. 9, 1397–1402 (2011).

    Article  PubMed  Google Scholar 

  36. Curtit, E. et al. Discordances in estrogen receptor status, progesterone receptor status, and HER2 status between primary breast cancer and metastasis. Oncologist 18, 667–674 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Park, S. et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J. Thorac. Oncol. 4, 809–815 (2009).

    Article  PubMed  Google Scholar 

  38. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. The Cancer Genome Atlas. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  41. Stephens, P.J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pellegata, N.S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl. Acad. Sci. USA 103, 15558–15563 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Milne, T.A. et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl. Acad. Sci. USA 102, 749–754 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Karnik, S.K. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl. Acad. Sci. USA 102, 14659–14664 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fisher, S. et al. A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries. Genome Biol. 12, R1 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. DePristo, M.A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pugh, T.J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Saunders, C.T. et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811–1817 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Chiang, D.Y. et al. High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat. Methods 6, 99–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Mermel, C.H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Caring for Carcinoid Foundation (S.L.A. and M.M.), the Raymond and Beverly Sackler Foundation for the Arts and Sciences (C.T., A. Karpathakis, S.L.A. and M.M.) and Cancer Research UK (C.T. and A. Karpathakis).

Author information

Authors and Affiliations

Authors

Contributions

J.M.F., A. Kiezun, A.H.R., R.S., S.L.A., C.R.H., M.K. and M.M. conceived and designed the experiments. J.M.F., A. Kiezun, A.H.R., S.S., C.S.P., Z.R.Q., A. Karpathakis, S.O., C.T., R.S., S.L.A., C.R.H., G.G., M.K. and M.M. analyzed the data. C.S.P., Z.R.Q., M.S.B., R.K., A.A.K., A. Karpathakis, V.M., T.C., J.P., N.P., S.M.H., L.K.B., M.S.L., T.P., A.M., A.S., K.C., S.L.C., A.I.O., S.F., R.T.J., D.V., G.S., T.M., M.C., D.C.C., A.S.B., S.O., C.T., R.S., S.L.A., C.R.H., G.G., M.K., J.G., L.G. and N.L. contributed reagents, materials and tools. E.N., D.A., R.O., E.S. and C.S. provided project management support. J.M.F., A. Kiezun, A.H.R., S.L.A., M.K. and M.M. wrote the manuscript with contributions from all other authors.

Corresponding authors

Correspondence to Matthew Kulke or Matthew Meyerson.

Ethics declarations

Competing interests

M.M. is a paid consultant for and equity holder in Foundation Medicine, a genomics-based oncology diagnostics company.

Supplementary information

Supplementary Figures

Supplementary Figures 1–5 (PDF 5046 kb)

Supplementary Tables

Supplementary Tables 1–16 (XLSX 1785 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Francis, J., Kiezun, A., Ramos, A. et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 45, 1483–1486 (2013). https://doi.org/10.1038/ng.2821

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2821

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer