title: Analysis of protein expression and gene mutation of c-kit in colorectal neuroendocrine carcinomas.
abstract: Primary neuroendocrine carcinomas of the colon are rare but highly aggressive malignancies. The recent observations that c-kit protooncogene, a tyrosine kinase, is overexpressed in a subset of small cell lung cancer and that selective kinase inhibitors block the in vitro growth of small cell lung cancer cell lines prompted us to investigate the expression and mutation status of the c-kit gene in colorectal neuroendocrine carcinomas. Sixty-six cases of primary colorectal neuroendocrine carcinoma were collected from 13 institutions, including 36 small cell carcinomas and 30 moderately differentiated neuroendocrine carcinomas. Immunohistochemical studies using a polyclonal antibody against c-kit protein (CD117) demonstrated a strong and diffuse cytoplasmic staining in 15 cases (23%), which were relatively equally distributed in the small cell and moderately differentiated subgroups. As controls, 25 conventional colorectal adenocarcinomas, 26 colorectal adenomas and 19 colorectal carcinoid tumors were all negative, whereas 15 gastrointestinal stromal tumors were all positive, for kit expression. In contrast to gastrointestinal stromal tumors, kit-overexpressing neuroendocrine carcinomas showed no mutations in the juxtamembrane domain (exon 11) of the c-kit gene as determined by mutational analysis. Kaplan-Meier analysis with the log-rank test revealed that the patients with kit-positive tumors did not differ significantly in survival from those with kit-negative tumors (P = 0.77). These results indicate that c-kit overexpression observed in a subset of colorectal neuroendocrine carcinomas may not be mediated via activating mutations, and does not appear to be an initiating event during tumorigenesis because of lack of c-kit expression in other types of colorectal epithelial neoplasms. More importantly, our observations may have potential therapeutic implications since specific tyrosine kinase inhibitors have shown promise in the management of patients with kit-expressing malignancies.
authors.affiliation: Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Olaronke
authors.initials: O
authors.lastname: Akintola-Ogunremi
authors.forename: John D
authors.initials: JD
authors.lastname: Pfeifer
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Tan
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Zhu
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.forename: John R
authors.initials: JR
authors.lastname: Goldblum
authors.forename: Lawrence
authors.initials: L
authors.lastname: Burgart
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Montgomery
authors.forename: David
authors.initials: D
authors.lastname: Lewin
authors.forename: Kay
authors.initials: K
authors.lastname: Washington
authors.forename: Mary
authors.initials: M
authors.lastname: Bronner
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Xiao
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.forename: Laura
authors.initials: L
authors.lastname: Lamps
authors.forename: Audrey
authors.initials: A
authors.lastname: Lazenby
authors.forename: Hanlin L
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D016019:Survival Analysis
chemical_list: D019009:Proto-Oncogene Proteins c-kit