title: Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations.
abstract: Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk. We describe a father and son with extensive hamartomatous gastrointestinal polyposis who both developed early-onset esophageal cancer. Exome sequencing identified a novel germline PTEN frameshift mutation (c.568_569insC, p.V191Sfs*11). In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals. Fluorescence in situ hybridization for PTEN in the resected esophageal cancer specimen demonstrated no PTEN copy loss in malignant cells; however, results of an immunohistochemical analysis demonstrated a loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, association between esophageal adenocarcinoma and these syndromes has not been previously reported. Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype. Alternatively, because simultaneous disruption of both the PTEN and TGF-β/SMAD4 pathways is associated with development of esophageal cancer in a mouse model and because SMAD4 mutations cause gastrointestinal hamartomas in juvenile polyposis syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype.
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Sherman
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Maxwell
authors.affiliation: Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Qining
authors.initials: Q
authors.lastname: Qian
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellizzi
authors.affiliation: Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Braun
authors.affiliation: Department of Thoracic Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Iannettoni
authors.affiliation: Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. Electronic address: james-howe@uiowa.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D001483:Base Sequence; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D016368:Frameshift Mutation; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D044483:Intestinal Polyposis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497806:SMAD7 protein, human; D051906:Smad7 Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Cowden syndrome; PTEN; PTEN hamartoma tumor syndrome; SMAD7; esophageal cancer