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.

Keywords: Cowden syndrome; PTEN; PTEN hamartoma tumor syndrome; SMAD7; esophageal cancer.

Figure 1

(A) PTEN Hamartoma Tumor Syndrome and esophageal cancer family. Solid shading indicates affected individuals who both had colonic polyposis and esophageal adenocarcinoma. Individuals I-1, I-2, II-3, and III-1 had no apparent symptoms. The proband, (Patient II-2), had esophageal cancer, thyroid cancer, and multiple juvenile polyps of the colon. Patient III-2 also had esophageal cancer, as well as ganglioneuromatous polyps of the stomach, duodenum and colon, and thyroid nodules. (B) Colectomy specimen from Patient III-2, showing diffuse polypoid ganglioneuromas with the arrow marking a representative ganglioneuromatous polyp. (C) Forward (Fwd.) and reverse (Rev.) Sanger sequencing confirmed a germline PTEN frameshift mutation in Patients II-2 and III-2.

Figure 2

Immunohistochemical staining reveals weak PTEN protein expression throughout Patient II-2’s normal thyroid tissue (A), which is absent in his papillary thyroid cancer (B). Both images magnified 400×. Similar loss of PTEN expression is observed in esophageal adenocarcinoma cells from Patient III-2 (C, 200× magnification). In (B) and (C), non-cancerous endothelial cells retain PTEN expression. Esophageal adenocarcinoma from Patient III-2 demonstrates preserved expression of SMAD7 protein, with staining similar to that seen in surrounding cells (D, 200× magnification). Fluorescent in-situ hybridization demonstrates two PTEN copies in malignant esophageal cancer cells from Patient III-2 (E). In these representative cells, red fluorescence marks PTEN and green fluorescence marks the chromosome 10 centromere.