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Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations.
- Source :
-
Cancer genetics [Cancer Genet] 2015 Jan-Feb; Vol. 208 (1-2), pp. 41-6. Date of Electronic Publication: 2014 Nov 15. - Publication Year :
- 2015
-
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&#95;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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Adenocarcinoma metabolism
Adenocarcinoma pathology
Adult
Base Sequence
Esophageal Neoplasms metabolism
Esophageal Neoplasms pathology
Exome genetics
Family Health
Fatal Outcome
Female
Frameshift Mutation
Gastrointestinal Neoplasms genetics
Gastrointestinal Neoplasms metabolism
Gastrointestinal Neoplasms pathology
Genotype
Germ-Line Mutation
Hamartoma Syndrome, Multiple metabolism
Hamartoma Syndrome, Multiple pathology
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Intestinal Polyposis genetics
Intestinal Polyposis metabolism
Intestinal Polyposis pathology
Male
Middle Aged
Mutation, Missense
PTEN Phosphohydrolase metabolism
Pedigree
Sequence Analysis, DNA methods
Smad7 Protein metabolism
Adenocarcinoma genetics
Esophageal Neoplasms genetics
Hamartoma Syndrome, Multiple genetics
Mutation
PTEN Phosphohydrolase genetics
Smad7 Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2210-7762
- Volume :
- 208
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Cancer genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25554686
- Full Text :
- https://doi.org/10.1016/j.cancergen.2014.11.002