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Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors

  • Translational Research and Biomarkers
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Abstract

Background

Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.

Methods

This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype–phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.

Results

Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.

Conclusion

This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

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Acknowledgment

The authors thank Mrs. Birgitta Bondesson for excellent technical assistance and logistical support. This study was supported by Grants from the Swedish Cancer Society, the Selander Foundation, and the Lions club of Uppsala. Peyman Björklund is a Swedish Cancer Society Investigator.

Conflict of interest

There are no conflicts of interest.

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    Authors and Affiliations

    1. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

      Joakim Crona MD, PhD, Tobias Gustavsson BSc, Olov Norlén MD, PhD, Katarina Edfeldt MSc, PhD, Tobias Åkerström MD, Gunnar Westin PhD, Per Hellman MD, PhD, Peyman Björklund PhD & Peter Stålberg MD, PhD

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    1. Joakim Crona MD, PhD
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    2. Tobias Gustavsson BSc
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    3. Olov Norlén MD, PhD
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    4. Katarina Edfeldt MSc, PhD
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    5. Tobias Åkerström MD
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    Correspondence to Joakim Crona MD, PhD.

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    Joakim Crona and Tobias Gustavsson have contributed equally to this study.

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    Crona, J., Gustavsson, T., Norlén, O. et al. Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors. Ann Surg Oncol 22 (Suppl 3), 1428–1435 (2015). https://doi.org/10.1245/s10434-014-4351-9

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    • DOI: https://doi.org/10.1245/s10434-014-4351-9

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