title: Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor.
abstract: OBJECTIVE
  Small intestinal neuroendocrine tumors (SINET) are the commonest malignancy of the small intestine; however, underlying pathogenic mechanisms remain poorly characterized. Whole-genome and -exome sequencing has demonstrated that SINETs are mutationally quiet, with the most frequent known mutation in the cyclin-dependent kinase inhibitor 1B gene (CDKN1B) occurring in only ∼8% of tumors, suggesting that alternative mechanisms may drive tumorigenesis. The aim of this study is to perform genome-wide molecular profiling of SINETs in order to identify pathogenic drivers based on molecular profiling. This study represents the largest unbiased integrated genomic, epigenomic, and transcriptomic analysis undertaken in this tumor type.
  
  
  METHODS
  Here, we present data from integrated molecular analysis of SINETs (n = 97), including whole-exome or targeted CDKN1B sequencing (n = 29), HumanMethylation450 BeadChip (Illumina) array profiling (n = 69), methylated DNA immunoprecipitation sequencing (n = 16), copy-number variance analysis (n = 47), and Whole-Genome DASL (Illumina) expression array profiling (n = 43).
  
  
  RESULTS
  Based on molecular profiling, SINETs can be classified into three groups, which demonstrate significantly different progression-free survival after resection of primary tumor (not reached at 10 years vs. 56 months vs. 21 months, P = 0.04). Epimutations were found at a recurrence rate of up to 85%, and 21 epigenetically dysregulated genes were identified, including CDX1 (86%), CELSR3 (84%), FBP1 (84%), and GIPR (74%).
  
  
  CONCLUSIONS
  This is the first comprehensive integrated molecular analysis of SINETs. We have demonstrated that these tumors are highly epigenetically dysregulated. Furthermore, we have identified novel molecular subtypes with significant impact on progression-free survival.
authors.affiliation: University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Karpathakis
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Dibra
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Chistodoulos
authors.initials: C
authors.lastname: Pipinikas
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Morris
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua
authors.initials: J
authors.lastname: Francis
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.affiliation: University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom.
authors.forename: Dalvinder
authors.initials: D
authors.lastname: Mandair
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: Marinos
authors.initials: M
authors.lastname: Pericleous
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: Mullan
authors.initials: M
authors.lastname: Mohmaduvesh
authors.affiliation: UHN Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Serra
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: Olagunju
authors.initials: O
authors.lastname: Ogunbiyi
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: TuVinh
authors.initials: T
authors.lastname: Luong
authors.affiliation: UHN Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kulke
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: Christos
authors.initials: C
authors.lastname: Toumpanakis
authors.affiliation: University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.affiliation: The Royal Free Hospital, London, United Kingdom.
authors.forename: Martyn
authors.initials: M
authors.lastname: Caplin
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: University College London, London, United Kingdom. The Royal Free Hospital, London, United Kingdom. christina.thirlwell@ucl.ac.uk.
authors.forename: Christina
authors.initials: C
authors.lastname: Thirlwell
mesh_terms: D000328:Adult; D000368:Aged; D002887:Chromosomes, Human, Pair 18; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007414:Intestinal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D015203:Reproducibility of Results
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27