At the recent annual meeting of the Society of
Gynecologic Oncologists (SGO), researchers announced findings
suggesting that the putative tumor-suppressor genethe fragile
histidine triad (FHIT) genemay be central to the development of
cervical cancer. The gene appears to be particularly susceptible to
carcinogens from cigarette smoke, and cigarette smoking is an
epidemiologic risk factor for cervical cancer.
Cigarette smoke carcinogens have been found in cervical mucus. The
FHIT gene is frequently altered in smoking-associated lung cancer and
is located on chromosome 3p14.2, surrounding FRA3B, one of the most
fragile sites of the human genome and a known human papillomavirus
(HPV) integration site.
The human papilloma virus is detected in more than 90% of all
squamous cell carcinomas of the uterine cervix, and is thought to be
integral to the development of cervical cancer. However, the reported
annual rates of HPV infection are over 1,000 times higher than the
annual incidence of cervical cancer, and at least 90% of HPV
infections resolve spontaneously. Therefore, other carcinogenic
cofactors are important in the evolution of cervical cancer, one of
which is cigarette smoking.
Cigarette Smoking and the FHIT Gene
The study was conducted by Christine H. Holschneider,MD, Rae Lynn
Baldwin, MD, Jeffrey S. Epstein, MS, and Beth Y. Karlan, MD, of
Cedars Sinai Medical Center and the University of California, Los
Angeles; and Juan C. Felix, MD, University of Southern California.
The researchers hypothesized that cigarette smokingassociated
cervical cancer may share certain pathogenetic features with other
tobacco-associated malignancies. Studies of lung cancers and
premalignant pulmonary lesions have demonstrated a strong association
between cigarette smoking and alterations in the FHIT gene.
The researchers reviewed archival tissues of 37 patients (17 smokers,
20 nonsmokers) who had undergone radical hysterectomy for squamous
cell carcinoma of the cervix. Data on patient age, race, smoking
habits, tumor grade, and date of radical hysterectomy were extracted
from medical records. Patients were only included in the study if
their smoking status was clearly documented in at least two different
sites in the hospital chart, such as the admission records,
consultations, or anesthesia notes. From each specimen block,
contiguous sections were prepared and used for immunohistochemistry
and laser capture microdissection.
The human papillomavirus was detected in 92% of the tumors, 88% of
dysplasias, and 85% of nondysplastic epithelia adjacent to the tumor.
There was no significant difference in the HPV status of smokers vs
nonsmokers. However, a reduction of FHIT protein expression, as well
as homozygous deletions at the FHIT gene locus, occurred
significantly more frequently in the tumors of smokers vs nonsmokers.
The researchers are currently investigating whether FHIT is a
potential genetic link between cigarette smoking and cervical cancer.