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Regular Article |
From the Clinical Cancer Genetics and Human Cancer Genetics
Programs,*
Comprehensive Cancer Center, and the Division of
Human Genetics, Department of Internal Medicine, The Ohio State
University, Columbus, Ohio; the Department of Obstetrics and
Gynecology,
Nippon Medical School, Tokyo,
Japan; the Division of Hematology/Oncology,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts; the Department of Paediatrics and Child
Health,
Section of Medical and Molecular
Genetics, University of Birmingham Medical School, Birmingham, United
Kingdom; and the Cancer Research Campaign Human Cancer Genetics
Research Group,¶
University of Cambridge,
Cambridge, United Kingdom
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 Bannayan-Riley-Ruvalcaba syndrome. Among several series of
ovarian cancers, the frequency of loss of heterozygosity (LOH)
of markers flanking and within PTEN, is 
30 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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B. Kwabi-Addo, D. Giri, K. Schmidt, K. Podsypanina, R. Parsons, N. Greenberg, and M. Ittmann Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression PNAS, September 25, 2001; 98(20): 11563 - 11568. [Abstract] [Full Text] [PDF]
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