No Evidence of a Role for Mutations or Polymorphisms of the Follicle-Stimulating Hormone Receptor in Ovarian Granulosa Cell Tumors1
Peter J. Fuller2,
Karen Verity,
Yan Shen3,
Pamela Mamers,
Tom Jobling and
Henry G. Burger
Prince Henry’s Institute of Medical Research, Monash University,
and Department of Obstetrics and Gynecology, Monash Medical Center,
Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Dr. Peter J. Fuller, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail:
peter.fuller{at}med.monash.edu.au
The molecular pathogenesis of granulosa cell tumors of the ovaryis not
understood, although recent studies have shown that immunoreactive
inhibinsecretion by these tumors may be used as a tumor marker.
Granulosacell tumors exhibit many features of normal granulosa cells,
includinga response to FSH and inhibin secretion. FSH levels are
suppressedin patients with inhibin-secreting granulosa cell tumors,
suggestingFSH-independent growth of these tumors. Activating mutations
ofthe FSH receptor might, therefore, be involved in tumorigenesis.We
sought to identify mutations in the FSH receptor genes ofthese tumors
using PCR to amplify the exon encoding the transmembraneand
cytoplasmic domains from the tumor DNA. Analysis of theamplicons for
single strand conformational polymorphisms anddirect sequencing
confirmed a previously reported polymorphismin the C-terminal region
of the receptor, but did not identifytumor-specific missense mutations
and/or polymorphisms. In addition,ribonucleic acid from 3 granulosa
cell tumors was used to confirmexpression of the FSH receptor;
expression was unexpectedlyalso observed in several ovarian mucinous
cystadenocarcinomasused as controls. In conclusion, our failure to
identify activatingmutations of the FSH receptor in 15 granulosa cell
tumors arguesagainst a role for the FSH receptor in tumorigenesis and
suggeststhat some subsequent component of this signal transduction
pathwaymay be activated.
This article has been cited by other articles:
M.-N. Lague, M. Paquet, H.-Y. Fan, M. J. Kaartinen, S. Chu, S. P. Jamin, R. R. Behringer, P. J. Fuller, A. Mitchell, M. Dore, et al. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression
Carcinogenesis,
November 1, 2008;
29(11):
2062 - 2072.
[Abstract][Full Text][PDF]
M. Zhang, Y.-X. Tao, G. L. Ryan, X. Feng, F. Fanelli, and D. L. Segaloff Intrinsic Differences in the Response of the Human Lutropin Receptor Versus the Human Follitropin Receptor to Activating Mutations
J. Biol. Chem.,
August 31, 2007;
282(35):
25527 - 25539.
[Abstract][Full Text][PDF]
A. M Dorward, K. L Shultz, and W. G Beamer LH analog and dietary isoflavones support ovarian granulosa cell tumor development in a spontaneous mouse model
Endocr. Relat. Cancer,
June 1, 2007;
14(2):
369 - 379.
[Abstract][Full Text][PDF]
J.-H. Choi, A. S. T. Wong, H.-F. Huang, and P. C. K. Leung Gonadotropins and Ovarian Cancer
Endocr. Rev.,
June 1, 2007;
28(4):
440 - 461.
[Abstract][Full Text][PDF]
C.Q. Yang, K.Y.K. Chan, H.Y.S. Ngan, U.S. Khoo, P.M. Chiu, Q.K.Y. Chan, W.C. Xue, and A.N.Y. Cheung Single nucleotide polymorphisms of follicle-stimulating hormone receptor are associated with ovarian cancer susceptibility
Carcinogenesis,
July 1, 2006;
27(7):
1502 - 1506.
[Abstract][Full Text][PDF]
N. Kalfa, A. Ecochard, C. Patte, P. Duvillard, F. Audran, C. Pienkowski, E. Thibaud, R. Brauner, C. Lecointre, D. Plantaz, et al. Activating Mutations of the Stimulatory G Protein in Juvenile Ovarian Granulosa Cell Tumors: A New Prognostic Factor?
J. Clin. Endocrinol. Metab.,
May 1, 2006;
91(5):
1842 - 1847.
[Abstract][Full Text][PDF]
M. Anttonen, L. Unkila-Kallio, A. Leminen, R. Butzow, and M. Heikinheimo High GATA-4 Expression Associates with Aggressive Behavior, whereas Low Anti-Mullerian Hormone Expression Associates with Growth Potential of Ovarian Granulosa Cell Tumors
J. Clin. Endocrinol. Metab.,
December 1, 2005;
90(12):
6529 - 6535.
[Abstract][Full Text][PDF]
D. Boerboom, M. Paquet, M. Hsieh, J. Liu, S. P. Jamin, R. R. Behringer, J. Sirois, M. M. Taketo, and J. S. Richards Misregulated Wnt/{beta}-Catenin Signaling Leads to Ovarian Granulosa Cell Tumor Development
Cancer Res.,
October 15, 2005;
65(20):
9206 - 9215.
[Abstract][Full Text][PDF]
S. Sudo, M. Kudo, S.-i. Wada, O. Sato, A. J.W. Hsueh, and S. Fujimoto Genetic and functional analyses of polymorphisms in the human FSH receptor gene
Mol. Hum. Reprod.,
October 1, 2002;
8(10):
893 - 899.
[Abstract][Full Text][PDF]
Y.-X. Tao, D. Mizrachi, and D. L. Segaloff Chimeras of the Rat and Human FSH Receptors (FSHRs) Identify Residues that Permit or Suppress Transmembrane 6 Mutation-Induced Constitutive Activation of the FSHR via Rearrangements of Hydrophobic Interactions Between Helices 6 and 7
Mol. Endocrinol.,
August 1, 2002;
16(8):
1881 - 1892.
[Abstract][Full Text][PDF]
G. E. Owens, R. A. Keri, and J. H. Nilson Ovulatory Surges of Human CG Prevent Hormone-Induced Granulosa Cell Tumor Formation Leading to the Identification of Tumor-Associated Changes in the Transcriptome
Mol. Endocrinol.,
June 1, 2002;
16(6):
1230 - 1242.
[Abstract][Full Text][PDF]
S. Chu, S. Rushdi, E.T. Zumpe, P. Mamers, D.L. Healy, T. Jobling, H.G. Burger, and P.J. Fuller FSH-regulated gene expression profiles in ovarian tumours and normal ovaries
Mol. Hum. Reprod.,
May 1, 2002;
8(5):
426 - 433.
[Abstract][Full Text][PDF]
P. J. Fuller, E. T. Zumpe, S. Chu, P. Mamers, and H. G. Burger Inhibin-Activin Receptor Subunit Gene Expression in Ovarian Tumors
J. Clin. Endocrinol. Metab.,
March 1, 2002;
87(3):
1395 - 1401.
[Abstract][Full Text][PDF]
C. S. Choong, P. J. Fuller, S. Chu, Y. Jeske, F. Bowling, R. Brown, P. Borzi, N. D. Balazs, R. Suppiah, A. M. Cotterill, et al. Sertoli-Leydig Cell Tumor of the Ovary, a Rare Cause of Precocious Puberty in a 12-Month-Old Infant
J. Clin. Endocrinol. Metab.,
January 1, 2002;
87(1):
49 - 56.
[Abstract][Full Text][PDF]
A. P. N. Themmen and I. T. Huhtaniemi Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function
Endocr. Rev.,
October 1, 2000;
21(5):
551 - 583.
[Abstract][Full Text]
J. L. Juengel, L. D. Quirke, D. J. Tisdall, P. Smith, N. L. Hudson, and K. P. McNatty Gene Expression in Abnormal Ovarian Structures of Ewes Homozygous for the Inverdale Prolificacy Gene
Biol Reprod,
June 1, 2000;
62(6):
1467 - 1478.
[Abstract][Full Text]
S. Chu, P. Mamers, H. G. Burger, and P. J. Fuller Estrogen Receptor Isoform Gene Expression in Ovarian Stromal and Epithelial Tumors
J. Clin. Endocrinol. Metab.,
March 1, 2000;
85(3):
1200 - 1205.
[Abstract][Full Text]
H. Zhang, M. Vollmer, M. De Geyter, Y. Litzistorf, A. Ladewig, M. Durrenberger, R. Guggenheim, P. Miny, W. Holzgreve, and C. De Geyter Characterization of an immortalized human granulosa cell line (COV434)
Mol. Hum. Reprod.,
February 1, 2000;
6(2):
146 - 153.
[Abstract][Full Text][PDF]
S. Hussein, S. Chu, and P. J. Fuller Comment on Analysis of Mutations in Genes of the Follicle-Stimulating Hormone Receptor in Ovarian Granulosa Cell Tumors
J. Clin. Endocrinol. Metab.,
October 1, 1999;
84(10):
3852 - 3853.
[Full Text][PDF]
M. J. Ligtenberg, M. Siers, A. P. N. Themmen, T. G. Hanselaar, W. Willemsen, and H. G. Brunner Analysis of Mutations in Genes of the Follicle-Stimulating Hormone Receptor Signaling Pathway in Ovarian Granulosa Cell Tumors
J. Clin. Endocrinol. Metab.,
June 1, 1999;
84(6):
2233 - 2234.
[Abstract][Full Text]
