title: Familial gastrointestinal stromal tumors, lentigines, and café-au-lait macules associated with germline c-kit mutation treated with imatinib.
abstract: BACKGROUND
  Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes.
  
  
  METHODS
  We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings.
  
  
  RESULTS
  Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them.
  
  
  CONCLUSIONS
  A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.
authors.affiliation: Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Laxmisha
authors.initials: L
authors.lastname: Chandrashekar
authors.affiliation: Department of Health Sciences, Medical Genetics, Università degli Studi di Milano, Milano, Italy.|Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.affiliation: Department of Health Sciences, Medical Genetics, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Colombo
authors.affiliation: Department of Health Sciences, Medical Genetics, Università degli Studi di Milano, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fontana
authors.affiliation: Department of Health Sciences, Medical Genetics, Università degli Studi di Milano, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Devinder M
authors.identifier: http://orcid.org/0000-0003-2207-8848
authors.initials: DM
authors.lastname: Thappa
authors.affiliation: Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Medha
authors.initials: M
authors.lastname: Rajappa
authors.affiliation: Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Kalai Selvi
authors.initials: KS
authors.lastname: Rajendiran
authors.affiliation: Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Gubbi Shamanna
authors.initials: GS
authors.lastname: Sreenath
authors.affiliation: Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Kate
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019080:Cafe-au-Lait Spots / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007911:Lentigo / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D010375:Pedigree; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit