Sex steroid hormones inﬂuence the risk for cervical cancer:
modulation by haptoglobin genetic polymorphism
Maria Clara Bicho
, Alda Pereira da Silva
, Ana Matos
, Rui Medeiros Silva
Manuel Diamantino Bicho
Instituto Portugueˆs de Oncologia Francisco Gentil (IPO-FG), Lisbon, Portugal
Genetics Laboratory & Metabolism and Endocrinology Centre, Faculty of Medicine, Lisbon University Medical School, Av. Prof.
Egas Moniz, 1649-028, Lisbon, Portugal
Instituto Portugueˆs de Oncologia Francisco Gentil IPO-FG, Oporto, Portugal
Received 15 October 2008; accepted 12 February 2009
Sex steroid hormones ingestion (contraceptives and replacement therapy) may inﬂuence cervical
carcinogenesis. Haptoglobin (Hp), an acute phase protein that has genetic polymorphism, can inﬂu-
ence immune response to tumor. Our objective was to study the inﬂuence of haptoglobin genetic
polymorphism on the risk for development of cervical cancer dependent on sex steroid hormones.
A total of 492 Caucasian women, 196 pathologic [high-grade squamous intraepithelial lesions and
invasive cervical cancer (HSIL þ ICC)], ranging in age from 18 to 81 years, were phenotyped for
plasma Hp using a polyacrylamide gel electrophoresis method. The effect of the interaction
between the Hp genetic phenotype and steroid hormone therapy was analyzed using a multinomial
logistic regression. Hp 1/1 genetic phenotype was associated with the risk for cervical cancer of
steroid hormone ingestion: general risk odds ratio (OR)55.388, P ! 0.001; for the interaction with
carriers of Hp 1/1, OR56.765, P ! 0.001; with carriers of Hp 2/1, OR56.499, P ! 0.001; and
with carriers of Hp 2/2, OR53.903, P 5 0.001. The linear trend of risks that result from that inter-
action is also signiﬁcant (c2 5 31.8, P ! 0.001). The higher risk for HSIL þ ICC observed in
carriers of increasing allele 1 of Haptoglobin probably results from the intense immune suppressor
effect of this form of Hp, in addition to that of steroid hormones ingestion. Ó 2009 Elsevier Inc.
All rights reserved.
Cervical cancer is the second most common malignant
disease among women worldwide, which is caused by
several oncogenic types of human papillomavirus (HPV)
The high-risk HPV, such as HPV-16 and HPV-18, are
found in 80e90% of invasive cancers, as well as in distinctive
premalignant stages of cervical intraepithelial neoplasia
(CIN) . Only a minority of women who have been infected
with high-risk types of HPV present with high-grade squa-
mous intraepithelial lesions (HSIL), which on average take
decades to develop into invasive cervical cancer (ICC)
through a multistep, progressive hystopathologic disease
pattern that involves the acquisition of multiple secondary
genetic changes . This indicates that the development of
cervical cancer is a multifactorial process that implicates
the contribution of other factors besides oncogenic HPV.
These cofactors are both environmental (smoking habits,
ingestion of sex steroid hormones, nutrition) and genetic
Among these cofactors, which are relevant for cervical
carcinogenesis, steroid hormones (estrogen and proges-
terone) are thought to play a role in the establishment
and/or progression of this disease. The high-risk, HPV-in-
fected women taking estradiol (E
) develop HSIL lesions
that progress to invasive ones at the transformation zone
(estrogen-sensitive region), which is the location implicated
in the genesis of cervical cancer [3,4]. Estrogen also affects
the type of immune response, which can affect the persis-
tence of HPV infection and the anti-tumor response [5,6].
The cervix is a crucial zone of the female body that has
* Corresponding author. Tel.: þ00351217999452; fax: þ00351217999451.
E-mail address: email@example.com (Manuel Diamantino Bicho).
0165-4608/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved.
Cancer Genetics and Cytogenetics 191 (2009) 85e89