title: Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors.
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.
  
  
  CONCLUSIONS
  This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. joakim.crona@surgsci.uu.se.
authors.forename: Joakim
authors.initials: J
authors.lastname: Crona
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gustavsson
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Norlén
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Edfeldt
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Åkerström
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westin
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stålberg
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018740:Genetic Heterogeneity; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27