Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations.
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.
['Sherman|Scott K|SK|', 'Maxwell|Jessica E|JE|', 'Qian|Qining|Q|', 'Bellizzi|Andrew M|AM|', 'Braun|Terry A|TA|', 'Iannettoni|Mark D|MD|', 'Darbro|Benjamin W|BW|', 'Howe|James R|JR|']
D000230:Adenocarcinoma D000328:Adult D001483:Base Sequence D004938:Esophageal Neoplasms D059472:Exome D005192:Family Health D017809:Fatal Outcome D005260:Female D016368:Frameshift Mutation D005770:Gastrointestinal Neoplasms D005838:Genotype D018095:Germ-Line Mutation D006223:Hamartoma Syndrome, Multiple D006801:Humans D007150:Immunohistochemistry D017404:In Situ Hybridization, Fluorescence D044483:Intestinal Polyposis D008297:Male D008875:Middle Aged D009154:Mutation D020125:Mutation, Missense D051059:PTEN Phosphohydrolase D010375:Pedigree D017422:Sequence Analysis, DNA D051906:Smad7 Protein
esophageal cancer PTEN SMAD7 PTEN hamartoma tumor syndrome Cowden syndrome