title: In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components.
abstract: Neuroendocrine carcinomas (NECs) of the colorectum are rare but highly aggressive neoplasms. These tumors show some shared genetic alterations with colorectal adenocarcinomas, and most of them have adjacent glandular adenoma or adenocarcinoma components. However, genetic data on colorectal NECs still are sparse and insufficient for definite conclusions regarding their molecular origin. Based on morphological characterization, panel and whole-exome sequencing, we here present results from an in-depth analysis of a collection of 15 colorectal NECs with glandular components, 10 of which by definition were mixed adenoneuroendocrine carcinomas (MANECs). Among shared genetic alterations of both tumor components, we most frequently found TP53, KRAS and APC mutations that also had highest allele frequencies. Mutations exclusive to glandular or neuroendocrine components outnumbered shared mutations but occurred at lower allele frequencies. Our findings not only provide additional evidence for a common clonal origin of colorectal NECs and adjacent glandular tumor components, but strongly suggest their development through the classical adenoma-carcinoma sequence. Moreover, our data imply early separation of glandular and neuroendocrine components during malignant transformation with subsequent independent mutational evolution.
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.
authors: Christine
authors: C
authors: Woischke
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.
authors: Christian W
authors: CW
authors: Schaaf
authors: Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.|Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors: Hui-Min
authors: HM
authors: Yang
authors: Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany.
authors: Michael
authors: M
authors: Vieth
authors: Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany.
authors: Lothar
authors: L
authors: Veits
authors: Institut für Pathologie, St Vincentius-Kliniken, Karlsruhe, Germany.
authors: Helene
authors: H
authors: Geddert
authors: Institut für Pathologie, Klinikum Augsburg, Augsburg, Germany.
authors: Bruno
authors: B
authors: Märkl
authors: Pathologicum Augsburg, Augsburg, Germany.
authors: Peter
authors: P
authors: Stömmer
authors: Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.
authors: David F
authors: DF
authors: Schaeffer
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.
authors: Matthias
authors: M
authors: Frölich
authors: Laboratory for Functional Genome Analysis (LAFUGA), at the Gene Center, Ludwig-Maximilians-Universität (LMU), München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Helmut
authors: H
authors: Blum
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU), München, Germany.
authors: Sebastian
authors: S
authors: Vosberg
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU), München, Germany.
authors: Philipp A
authors: PA
authors: Greif
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: A
authors: Jung
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Thomas
authors: T
authors: Kirchner
authors: Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David
authors: D
authors: Horst
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)