Cancer Prevention Research
Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar
Alterations in p53, ras, and HER-2/neu
Amy A. Hakim,1Catherine P. Barry,2H. John Barnes,3Kenneth E. Anderson,4James Petitte,4
Regina Whitaker,5Jonathan M. Lancaster,6Robert M. Wenham,6Donna K. Carver,4
Jane Turbov,1Andrew Berchuck,5Levy Kopelovich7and Gustavo C. Rodriguez1
We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu
oncogenes in chicken ovarian cancers to determine if these tumors have genetic altera-
tions similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor
suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequen-
cing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two se-
parate 2-year chemoprevention trials. Birds in trial B had approximately twice as many
lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu
oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Altera-
tions in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 altera-
tions varied according to the number of lifetime ovulations, ranging from 14% in trial A to
96% in trial B (P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%)
tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovar-
ian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human
ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and
correlate with the number of lifetime ovulations. Ras mutations are rare, similar to
high-grade human ovarian cancers. HER-2/neu overexpression is common and may re-
present a marker to exclude an oviductal origin in cancers involving both the ovary and
Epithelial ovarian cancer remains a highly lethal malignancy.
It is the fifth leading cause of cancer deaths among women in
the United States and causes more deaths than all other gyne-
cologic malignancies combined (1). Major advances in our un-
derstanding and treatment of ovarian cancer have occurred
over the past decade, yet the long-term cure rate of women
with this disease has only improved modestly. The feasibility
of early detection is uncertain, and highly effective curative
therapy for women who present with metastatic disease is
The pathogenesis of ovarian cancer is not completely
derstood, but it is believed that the process of ovulation leads
to genetic damage in the ovarian epithelium. Ovarian cancer
risk has been shown to correlate with the number
tory cycles in a woman's life time, whereas factors associated
with decreased ovulation such as increased parity, breast-feed-
ing, and oral contraceptive use have been shown to have a
protective effect (2). These observations have led to the “inces-
sant ovulation” hypothesis, which purports that repeated cy-
cles of epithelial disruption and repair may facilitate
neoplastic transformation of the ovarian epithelium in suscep-
tible individuals and that the risk of ovarian cancer may be
proportional to the number of ovulatory cycles in a woman's
lifetime (3). Repeated cycles of rupture and repair of the ovar-
ian epithelium associated with ovulation may predispose the
ovarian epithelium to DNA damage, inclusion cyst formation,
and dysplastic changes that can lead to neoplastic transfor-
mation. In addition, repetitive ovulation may expose the
ovarian epithelium to high levels of estradiol or gonadotro-
pins, which may increase ovarian cancer risk (4).
Until recently, the molecular events involved in the devel-
opment of human cancers were largely unknown. It is
now thought that most cancers arise due to inherited or
acquired alterations in oncogenes and tumor suppressor
Authors' Affiliations:1Department of Gynecologic Oncology, City of Hope,
California;2Department of Assay Research and Development, Abbott
Molecular, Des Plaines, Illinois;3College of Veterinary Medicine and
4Department of Poultry Science, North Carolina State University, Raleigh, North
Carolina;5Division of Gynecologic Oncology, Duke University Medical Center,
Durham, North Carolina;6Moffitt Cancer Center, University of South Florida,
Tampa, Florida; and7Chemoprevention Branch, National Cancer Institute,
Received 04/04/2008; revised 09/24/2008; accepted 09/27/2008; published
Grant support: Department of Defense grant USAMRMC/CDMRP-
OC990179; NIH grant N01 CN005114; and generous support from the Hertel-
Satter Foundation, Bear's Care, and Denyse King.
Requests for reprints: Gustavo C. Rodriguez, Division of Gynecologic
Oncology, Evanston Northwestern Healthcare, Northwestern University, Suite
1507, Walgreen Building, 2650 Ridge Avenue, Evanston, IL 60201. Phone:
847-570-2639; Fax: 847-733-5398; E-mail: email@example.com.
©2009 American Association for Cancer Research.
Cancer Prev Res 2009;2(2) February 2009www.aacrjournals.org
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Genetic Changes in Ovarian Cancers in Hens and Women
Cancer Prev Res 2009;2(2) February 2009www.aacrjournals.org