Scientists pinpoint
location
of possible third gene involved
in hereditary breast cancer
to Chromosome 13
BETHESDA, MD — Researchers in Finland,
Iceland, and Sweden, working with scientists at the National Human
Genome Research Institute (NHGRI) of the National Institutes of Health (NIH),
have found evidence of a new gene that appears to increase
susceptibility to hereditary breast cancer. The study examined women who
live in Nordic countries and who have three or more female family
members with breast cancer.
The finding, published in the August
15 issue of the Proceedings of the National Academy of Sciences (PNAS),
may help explain why some women with a family history of hereditary
breast cancer are at particularly high risk of developing the
potentially fatal disease, even when they lack mutations in two
previously identified breast cancer susceptibility genes, BRCA1 and
BRCA2.
Initially, spelling errors in the
genetic code of BRCA1 and BRCA2 were theorized to account for perhaps 90
percent of all hereditary breast cancers. However, more recent research
suggests that these two genes account for a significantly smaller
proportion of all hereditary breast cancers.
However, since all cancers are based
on genetic mutations in body cells, whether they are inherited or
triggered by aging or environmental factors, studies on cancer genetics
can lead to improved diagnosis and treatment.
While scientists reporting in the
current PNAS have not yet identified a third BRCA gene, they have
succeeded in pinpointing its probable location to chromosome 13, in an
interval of about five million base pairs. This is the same chromosome
that also contains the previously identified BRCA2 gene, discovered in
1995. (BRCA1, discovered in 1994, lies on chromosome 17.)
The human genome - the DNA on all
chromosomes - contains about 3 billion base pairs, misspellings and
deletions of which can increase susceptibility to diseases. Mutations of
BRCA1 and BRCA2 impair the body cells’ production of tumor suppressor
proteins.
"We've located what looks like a
very good region in the human genome in which to search for a third
breast cancer susceptibility gene," said Dr. Olli Kallioniemi,
senior scientist at NHGRI and corresponding author for the PNAS paper.
He is one of 35 scientists in 14 laboratories in the United States,
Finland, Sweden, Iceland and Germany who collaborated on the study.
"Our results are preliminary
results at this point," Dr. Kallioniemi stressed. "More work
must be done to confirm these results in other populations, and we have
yet to identify the DNA sequence of the gene. But if these results are
confirmed, this new gene could account for up to one third of the
hereditary breast cancer cases that cannot be explained by BRCA1 or
BRCA2 in the Nordic population."
"I greet these research findings
with a combination of excitement and caution,” said NHGRI Director Dr.
Francis Collins. “We’ve suspected for some time that hereditary
breast cancer is triggered by many susceptibility genes. Once we have
most of them identified and understood, we’ll be able to tailor
diagnosis and treatments much more effectively than we are able to do
now.”
“However, lots of research still
remains to be done,” he added.
The possible location of the suspected
gene was first identified by applying a technique called comparative
genomic hybridization, or CGH, to breast cancer tumor tissues. The
tissues came from 61 women with hereditary breast cancer, whose BRCA1
and BRCA2 genes had no detectable misspellings. All 61 women lived in
Finland, Sweden, and Iceland, and came from 37 families with three or
more hereditary breast cancer-affected female relatives.
Results from the CGH analysis revealed
that genetic material had been deleted in this region of chromosome 13
at an early stage in the development of the tumors, suggesting the
presence of a new cancer-causing gene there.
Further genetic studies were then
carried out on a larger group — 334 in number — of affected women
representing even more (77) Finnish, Icelandic, and Swedish families.
These families were specifically chosen because their strong family
history of breast cancer could not be attributed to the BRCA1 and BRCA2
genes. These studies employed linkage analysis, a complex statistical
method designed to determine the likelihood that a gene is inherited, or
passed along from one generation to the next, and to find the location
of this gene. The linkage analysis, in turn, supported the CGH evidence
for a new breast cancer susceptibility gene in the same region on
chromosome 13.
"While the probability of seeing
linkage evidence this strong just by chance is less than two out of a
thousand, we still need confirmation of this linkage in an independent
set of families," said Dr. Joan Bailey-Wilson, another co-author of
the study and a statistical geneticist at NHGRI.
Although this latest finding cannot be
applied now to diagnosis and treatment, it will help researchers narrow
their search for a new breast cancer gene, said Dr. Heli Nevanlinna, one
of the study's co-authors and a geneticist in the Department of
Obstetrics and Gynaecology at Helsinki University Central Hospital in
Finland.
"If a new gene is found, it will
provide another important means of diagnosis for families who are at
risk of developing hereditary breast cancer," Dr. Nevanlinna added.
If the scientists are able to identify
a third BRCA gene in the chromosome 13 region that they are studying,
they and other researchers will have to conduct much more research to
determine the new gene’s possible role in more heterogeneous
populations, such as in the United States. Mutations in BRCA1 and BRCA2
can occur in very different frequencies in different populations, and it
is likely the same would be true for any other breast cancer gene.
"There are probably other genes
besides this one," suggested Dr. Ake Borg, another of the study's
co-authors and a molecular geneticist in the Department of Oncology at
University Hospital in Lund, Sweden. "And the importance of each of
these genes may vary greatly, depending on the population."
The success of this study had much to
do with the Nordic populations being studied, noted Dr. Rosa Bjork
Barkardottir, a molecular biologist in the Department of Pathology at
University Hospital of Iceland in Reykjavik.
"It might have been difficult to
spot this candidate breast cancer region in other, more heterogeneous
populations, since especially the Finnish population and Icelandic
population are rather homogeneous," Dr. Barkardottir said.
"Also, compared to other populations, it is easier to identify
which families carry a mutation in BRCA1 or BRCA2 and which families
would be good in looking for a new BRCA gene."
In addition, Finland, Sweden, and
Iceland have extensive population records and cancer registries dating
back several generations. This information helps researchers determine
inheritance patterns for genetic-related diseases such as cancer.
For NHGRI researcher Dr. Tommi Kainu,
another co-author, much of the credit for the study should go both to
the researchers in the Nordic countries who recruited the breast cancer
families, and to the families themselves.
"When these families came through
cancer clinics and were diagnosed with breast cancer, they were asked to
fill out a family questionnaire on the presence of breast cancer in
their relatives," Dr. Kainu said. "And even in this difficult
time in dealing with their own disease, they took an active part in the
project. So, this study is also a tribute to them."
The next stage in the U.S.-Nordic
team's research will be to identify the precise sequence of DNA in the
region on chromosome 13 believed to contain the gene. In that region are
some five million base pairs — the chemical units of DNA. But within
this region, there may still be 100 to 150 genes that must be evaluated
one by one, in order to identify the precise gene responsible for the
breast cancer risk.
Because the Human Genome Project has
sequenced almost all of the human genetic code and made that data freely
available to all researchers, the scientists have the templates from
which to search, said Dr. Kallioniemi. "But that's not to say this
will be an easy job. There's still a lot of work to be done," he
added.
Institutions participating in the
study include NHGRI; the National Center for Biotechnology Information
(also part of NIH); Deutsches Krebsforschungzentrum, Heidelberg,
Germany; Tampere University and University Hospital, Finland; University
Hospital of Iceland, Reykjavik, Iceland; University Hospital, Lund,
Sweden; University Hospital, Umea, Sweden; Helsinki University Central
Hospital, Finland; and Turku University Hospital, Finland.
Support for the study was provided by
the NIH, the Nordic Cancer Society, the Finnish Cancer Society, the
Academy of Finland, the Sigrid Juselius Foundation, the Clinical
Research Funds of the Tampere and Helsinki University Hospitals, the
Icelandic Research Council, the Icelandic University Hospital Research
Fund, the Swedish Cancer Society, Mrs. Berta Kamprads Foundation, the
G.A.E. Nilsson Foundation, the F&M Bergqvist Foundation, the King
Gustav V's Jubilee Foundation, the Finnish Cultural Foundation, the Emil
Aaltonen Foundation, and the Maud Kuistila Foundation.
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