CHICAGOAn analysis of a six-generation extended
pedigree of 526 people from two small Turkish villages showed that mesothelioma
is genetically transmitted, and that building materials containing erionite may
be a cofactor.
The pedigree analysis of individuals from Karain (population
about 600) and Tuzköy (1,400) suggests that mesothelioma is probably
transmitted in an autosomal dominant way, Michele Carbone, MD, reported at a
conference on malignant mesothelioma hosted by the University of Chicago. [Look
for more reports from this meeting next month, including a consensus statement
on the role of SV40 in the disease.]
In the villages of Karain and Tuzköy, malignant mesothelioma
causes more than 50% of deaths, yet surrounding villages appear unaffected by
mesothelioma. This finding prompted researchers to look for the causative
agent, asbestos, in the two villages.
Investigators thought they had isolated the causative agent,
but subsequently discovered that asbestos was a natural component of the
volcanic terrain of this Cappadocian region. Since asbestos was found nearly
everywhere in the region, it could not account for the uniquely high incidence
of mesotheliomas in these two villages.
Further research implicated erionite, a mineral fiber that had
been detected in the lungs of several villagers. In addition, erionite was
found to cause mesothelioma tumors in rodents. However, erionite, like
asbestos, was also found to be common throughout most villages of this
region and thus, by itself, could not account for the high incidence of
Dr. Carbone, associate professor of pathology, Loyola
University Medical Center, Maywood, Illinois, noted that malignant mesothelioma
occurred mostly in specific homes where entire families had died from the
disease. Residents of the villages referred to these as "the houses of
On one visit to Karain, Dr. Carbone observed these houses
first-hand (see Figure). As he left one such house, a child immediately began
brushing a white powder, presumably containing erionite, from his jacket where
it had rubbed against the stone wall of the house.
Local authorities told Dr. Carbone that these "houses of
death" contained a greater amount of the causative agent, erionite, even
though neighboring houses appeared to have been built at about the same time
with what appeared to be the same type of stones.
Subsequent research confirmed the widespread use of
erionite-containing stones throughout other Turkish villages in the region,
with and without a high incidence of malignant mesothelioma deaths, thus ruling
out erionite as the sole causative agent.
Dr. Carbone began investigating the genetic evidence in Turkish
villages. Similar familial clusters of mesotheliomas had already been observed
in certain Western families, supporting a comparable hypothesis that genetic
transmission caused a predisposition in Western countries to asbestos or SV40
Gathering Genetic Data
To study the genetic hypothesis, one investigator from Dr.
Carbone’s research team, Iman Roushdy-Hammady, a PhD candidate in medical
anthropology, spent 2 years living in these Turkish villages, and several
months living in Sweden and Germany to study emigrants who originated from
these villages. Mr. Roushdy-Hammady was able to pierce substantial cultural
barriers to gathering epidemiologic and genetic data, which were then analyzed
by Dr. Carbone’s research team.
Dr. Carbone said that six families were identified in which
mesothelioma showed obvious familial clustering. The six families were linked
to one large six-generation extended pedigree of 526 individuals. Among these
individuals, Dr. Carbone identified 22 affected nuclear families with 87
children of affected parents41 of these 87 children had developed malignant
mesothelioma as adults.
The number of children with mesothelioma, 41 cases, did not
differ significantly from the number of cases that would have been predicted
from an autosomal dominant pattern of inheritance: 43.5 children (P = .5). This
finding suggests that malignant mesothelioma segregates in an autosomal
dominant pattern and that erionite might be a cofactor in genetically
predisposed individuals, Dr. Carbone said. He hopes that further information
will allow linkage analysis to identify those genetic-susceptibility factor(s)
that predispose individuals to malignant mesothelioma in Cappadocian villages.
"It is possible that the same gene that is genetically mutated in
Cappadocia may be the target of asbestos and SV40 carcinogenesis [the causes of
mesothelioma seen in developed countries]," he said. Isolation of this
putative gene may pave the way to understanding molecular pathogenesis of the