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.

Figure 1

Mutational analysis of 31 small bowel and 19 metastatic SI-NETs. a) Top panel shows the somatic mutation rate per megabase (Mb) of covered target sequence in the 50 cases. Middle panel shows the recurrent somatic mutation of CDKN1B and prominent somatic copy number alterations found in each tumor. Primary (TP) and metastatic (TM) tumors, sites and type of sequencing performed are indicated by colored boxes. b) Schematic representation of frameshift mutations identified in CDKN1B. c) Schematic of the hemizygous deletions identified targeting CDKN1B.

Figure 2

Somatic mutation and copy number discordance between primary and metastatic cases. a) Venn diagram depicting the concordance and discordance in somatic mutation calls in the primary or metastatic lesion analyzed in 5 cases. b) Copy number profiles for concordant and discordant primary and metastatic tumors.