Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations

Scott K Sherman; Jessica E Maxwell; Qining Qian; Andrew M Bellizzi; Terry A Braun; Mark D Iannettoni; Benjamin W Darbro; James R Howe

doi:10.1016/j.cancergen.2014.11.002

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Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations

Journal article

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Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations

Scott K Sherman, Jessica E Maxwell, Qining Qian, Andrew M Bellizzi, Terry A Braun, Mark D Iannettoni, Benjamin W Darbro and James R Howe

Cancer genetics, Vol.208(1), pp.41-46

2015

DOI: 10.1016/j.cancergen.2014.11.002

PMCID: PMC4355394

PMID: 25554686

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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.V191S_fs*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, immunohistochemistry demonstrated loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, esophageal adenocarcinoma 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 SMAD4 mutations cause gastrointestinal hamartomas in Juvenile Polyposis Syndrome, the SMAD7 mutation may represent an additional modifier of these individuals’ PTEN -mutant phenotype.

Esophageal Cancer

PTEN

Cowden Syndrome

PTEN Hamartoma Tumor Syndrome

SMAD7

Details

Title: Subtitle: Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations
Creators: Scott K Sherman - Department of General Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Jessica E Maxwell - Department of General Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Qining Qian - Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Andrew M Bellizzi - Department of Pathology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Terry A Braun - Department of Ophthalmology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Mark D Iannettoni - Department of Thoracic Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Benjamin W Darbro - Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
James R Howe - Department of General Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa, USA 52242
Resource Type: Journal article
Publication Details: Cancer genetics, Vol.208(1), pp.41-46
DOI: 10.1016/j.cancergen.2014.11.002
PMID: 25554686
PMCID: PMC4355394
NLM abbreviation: Cancer Genet
ISSN: 2210-7762
eISSN: 2210-7770
Grant note: DOI: 10.13039/100000002, name: NIH, award: 5T32#CA148062-04
Language: English
Date published: 2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Surgery
Record Identifier: 9984047996902771

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