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
"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
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
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
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
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
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. (A complete list of
authors is attached.)
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.