Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.
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"Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was originally described as a somatically mutated tumor-suppressor gene in brain, breast, and prostate cancers. Germline loss-of-function PTEN mutations are responsible for Cowden, Bannayan-Riley-Ruvalcaba, and other syndromes, known collectively as the PTEN hamartoma tumor syndrome (PHTS).    The autosomal-dominant and highly-penetrant PHTS conditions are characterized by a broad range of manifestations including macrocephaly, skin abnormalities, neurologic problems, and hamartomatous or ganglioneuromatous gastrointestinal polyposis. "
[Show abstract][Hide abstract] 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.
Cancer Genetics 11/2014; DOI:10.1016/j.cancergen.2014.11.002 · 2.98 Impact Factor
"Association studies have identified ATM, BRIP1, CASP8, CDH1, CHEK2, PALB2, PTEN, STK11, and TP53 as breast cancer susceptibility genes. Such mutations collectively account for 2.3% of familial risk of breast cancer, and together with BRCA1, BRCA2 and others have been implicated in high risk screening strategies5811121314151617181920. Nonetheless, significant proportion of the familial and non-familial breast cancer susceptibility remains unknown, suggesting plethora of genetic elements that need to be understood. "
[Show abstract][Hide abstract] ABSTRACT: Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2 (R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in cancer relevant genes with no prior reported association of point mutations with cancer, such as MTAP and MAGED1. For the first time, this study illustrates the power of RNA-sequencing in revealing the variation landscape of breast transcriptome and exemplifies analytical strategies to search regulatory interactions among cancer relevant molecules.
"Cowden’s syndrome is a rare familial autosomal disease that has been localized through several genetic studies to chromosome 10q23 and the tumor-suppressor gene PTEN.41–43 The phenotypic hallmarks of this disease include multiple facial papules, trichilemmomas, oral papillomas, and macrocephaly, though there are varied expressions of the disease even among families.42,44 Breast cancers are the most frequent malignancies reported to be associated with this syndrome, though various organ systems can be involved, including gastrointestinal and urogenital.41,43,44 "
[Show abstract][Hide abstract] ABSTRACT: There are several hereditary diseases that are a predisposition to early-onset tumors. These include syndromic conditions like neurofibromatosis 1 and 2, von Hippel-Lindau syndrome, Gorlin syndrome, multiple endocrine neoplasia, and familial adenomatous polyposis; and conditions which are usually not possible to diagnose clinically in a single individual, such as Lynch syndrome and BRCA1/2. Understanding of the mortality in hereditary cancer predisposing diseases is important for developing effective disease treatment programs. A number of studies have been undertaken to investigate the genetic predictors, prevalence and incidence, and treatment outcomes of these diseases; however, the majority examine only the most common of these diseases (eg, neurofibromatosis or BRCA), or look into postoperative survival. The mortality of individuals who are diagnosed with one of these hereditary diseases remains an area for investigation. This review is the first to attempt identification of studies investigating life expectancy in hereditary diseases which predispose to early-onset tumors.
The Application of Clinical Genetics 07/2013; 6:53-61. DOI:10.2147/TACG.S35605