Variant Manifestation of Cowden Disease in Japan: Hamartomatous Polyposis of the Digestive Tract with Mutation of the PTEN Gene

Kurose, Kouichi; Araki, Tsutomu; Matsunaka, Tsuyoshi; Takada, Yasuharu; Emi, Mitsuru

doi:10.1086/302207

Cited by 27 publications

(18 citation statements)

References 14 publications

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“…It is, therefore, vital that this patient be followed closely for development of Cowdenrelated cancers, especially those of the breast, thyroid, and endometrium, because the presence of a germline PTEN mutation is a sensitive molecular diagnostic marker for Cowden syndrome. 18,62 If our observations can be replicated, clinicians might wish to inquire about other features of Cowden syndrome and to take a good family history when faced with apparently sporadic ovarian cancer cases. Hereditary ovarian cancer occurs as a part of three clinically distinct syndromes, site-specific ovarian cancer and breast-ovarian cancer, both of which are because of germline mutations in BRCA1 and BRCA2 in Ͼ90% of such cases, 63 and hereditary nonpolyposis colorectal cancer.…”

Section: Discussionmentioning

confidence: 90%

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Kurose

Zhou

Araki

et al. 2001

The American Journal of Pathology

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219

145

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PTEN (MMAC1/TEP1), a tumor suppressor gene on chromosome subband 10q23.3, is variably mutated and/or deleted in a variety of human cancers. Germline mutations in PTEN, which encode a dual-specificity phosphatase, have been implicated in at least two hamartoma tumor syndromes that exhibit some clinical overlap, Cowden syndrome and BannayanRiley-Ruvalcaba syndrome. Among several series of ovarian cancers, the frequency of loss of heterozygosity (LOH) of markers flanking and within PTEN, is ϳ30 to 50%, and the somatic intragenic PTEN mutation frequency is <10%. In this study, we screened primary adenocarcinomas of the ovary for LOH of polymorphic markers within and flanking the PTEN gene and for intragenic mutations of the PTEN gene and compared them to PTEN expression using immunohistochemistry. Furthermore, we sought to detect the expression of the presumed downstream targets of PTEN, such as P-Akt, p27, and cyclin D1 by immunohistochemistry. LOH at 10q23 was observed in 29 of 64 (45%) cases. Of the 117 samples, 6 somatic intragenic PTEN mutations, 1 germline mutation, and 1 novel polymorphism were found in 7 (6%) patients. Immunostaining of 49 ovarian cancer samples revealed that 13 (27%) were PTEN immunostain-negative, 25 (51%) had reduced staining, and the rest (22%) were PTEN expression-positive. Among the 44 informative tumors assessed for 10q23 LOH and PTEN immunostaining, there was an association between 10q23 LOH and decreased or absent staining (P ‫؍‬ 0.0317). Of note, there were five (11%) tumors with neither mutation nor deletion that exhibited no PTEN expression and 10 (25%) others without mutation or deletion but had decreased PTEN expression. Among the 49 tumors available for immunohistochemistry, 28 (57%) showed P-Akt-positive staining, 24 (49%) had decreased p27 staining, and cyclin D1 was overexpressed in 35 (79%) cases. In general, P-Akt expression was inversely correlated with PTEN expression (P ‫؍‬ 0.0083). These data suggest that disruption of PTEN by several mechanisms, allelic loss, intragenic mutation, or epigenetic silencing, all contribute to epithelial ovarian carcinogenesis, and that epigenetic silencing is a significant mechanism. The Akt pathway is prominently involved, but clearly not in all cases. Surprisingly, despite in vitro demonstration that p27 and cyclin D1 lies downstream of PTEN and Akt, there was no correlation between p27 and cyclin D1 expression and PTEN or P-Akt status. Thus, in vivo, although PTEN and Akt play a prominent role in ovarian carcinogenesis, p27 and cyclin D1 might not be the primary downstream targets. Alternatively, these observations could also suggest that pathways involving other than Akt, p27 and cyclin D1 that lie downstream of PTEN play roles in ovarian carcinogenesis.

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Section: Discussionmentioning

confidence: 90%

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Kurose

Zhou

Araki

et al. 2001

The American Journal of Pathology

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219

145

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“…Some polyposis patients with germline PTEN mutations are reported to harbour only juvenile polyps without extraintestinal lesions;32 however, critical histological re-evaluation, complete physical examination and medical history often reveals evidence for the diagnosis of Cowden syndrome, in particular, as the penetrance of this syndrome is low in patients <20 years of age 31 34. Consequently, although some patients with germline PTEN mutations present with clinical signs not diagnostic for Cowden syndrome, they should be classified as having PTEN hamartoma tumour syndrome and medically managed as such 10 31…”

Section: Discussionmentioning

confidence: 99%

High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome

Aretz

Stienen

Uhlhaas

et al. 2007

Journal of Medical Genetics

214

170

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Background: In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown. Methods: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. Results: By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p,0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p,0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS). Conclusions: Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.

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“…PTEN is important in tumor suppression in the gastrointestinal tract, as shown in Cowden disease, where germline mutations of PTEN predispose to hamartomatous polyps throughout the gastrointestinal tract (9). Another mechanism for PTEN inactivation may be thought to exist in the cancer cells of both colorectal and gastric carcinomas in addition to mutation or deletion or hypermethylation of PTEN.…”

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confidence: 99%

Expression of NEDD‐1, a PTEN regulator, in gastric and colorectal carcinomas

Kim

Yoo²,

Jeong³

et al. 2008

APMIS

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Recent studies have disclosed that NEDD4-1 regulates PTEN activity by ubiquitination. NEDD4-1 negatively regulates PTEN in cytosol and acts as an oncogenic protein. By contrast, NEDD4-1 promotes PTEN nuclear import and acts as a tumor suppressor. Despite the importance of NEDD4-1 in PTEN regulation in cancer cells, expression of NEDD4-1 protein in cancer tissues is unknown. The aim of this study was to analyze NEDD4-1 expression in colorectal and gastric cancer tissues. We investigated NEDD4-1 protein expression in 103 colorectal and 60 gastric carcinoma tissues by immunohistochemistry using a tissue microarray approach. In the cancers, expression of NEDD4-1 was detected in 82 (80%) of the colorectal carcinomas and 45 (75%) of the gastric carcinomas in cytoplasm. By contrast, the normal mucosal cells of both stomach and colon showed no or very weak expression of NEDD4-1. There was no significant association of NEDD4-1 expression with clinicopathologic characteristics, including invasion, metastasis and stage. Our data indicate that NEDD4-1 overexpression is a feature of both colorectal and gastric carcinomas. The increased expression of NEDD4-1 in malignant gastric and colorectal cells compared to their normal epithelial cells suggests that NEDD4-1 expression may play a role in colorectal and gastric cancer development.

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Variant Manifestation of Cowden Disease in Japan: Hamartomatous Polyposis of the Digestive Tract with Mutation of the PTEN Gene

Cited by 27 publications

References 14 publications

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome

Expression of NEDD‐1, a PTEN regulator, in gastric and colorectal carcinomas

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