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 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.
Published in the August 15, 2000 issue of the Proceedings of the National Academy of Sciences (PNAS), this finding may help to 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.
While scientists have not yet identified a third BRCA gene, they have succeeded in pinpointing its probable location to chromosome 13, the same chromosome that contains the previously identified BRCA2 gene. Mutations of BRCA1 and BRCA2 impair the body's cell 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, former senior scientist at NHGRI. He is one of 35 scientists in 14 laboratories in the United States, Finland, Sweden, Iceland and Germany who collaborated on the study.
In the following discussion, study authors discuss the challenges in discovering the root causes of hereditary breast cancer.
Answered by: Dr. Olli Kallioniemi, former senior investigator, National Human Genome Research Institute (NHGRI)
There are clearly many high-risk breast cancer families where BRCA1 and BRCA2 do not seem to play a role. And many researchers in several large international consortiums have been trying to find clues for additional genes. The consensus that now prevails is that in at least half, if not more, of the hereditary breast cancer families, BRCA1 and BRCA2 are unlikely to contribute to the onset of their cancers.
At the same time, the consensus is building that there is no single strong breast cancer gene left to be discovered. BRCA1 and BRCA2 are very important genes. And for the rest of the high-risk families that are not accounted for by these two genes, it's most likely that there are many different genes, and that each may account for a small fraction of the remaining families. It's also very likely that the contribution of these genes varies dramatically, depending on which populations people are looking at.
Answered by: Dr. Tommi Kainu, former researcher, NHGRI
When we say hereditary breast cancer, we mean there's a genetic susceptibility to breast cancer. And according to a very recent study, this accounts for anywhere between 5 to 10 percent, to perhaps as much as 27 percent of all breast cancers. So, our research doesn't speak to other breast cancers that may be environmentally induced, just to hereditary breast cancer.
How do we determine if breast cancer is hereditary? As a starting point, we used the criteria that at least three first - or second-degree family members should have breast cancer - that means sisters, mothers, aunts, etc. BRCA1 and BRCA2 account for about 20 to 30 percent of such families, and what we were studying was the rest, the 70 to 80 percent of the hereditary breast cancer families.
Answered by: Dr. Ake Borg, molecular geneticist, University Hospital in Lund, Sweden
This study started a couple of years ago when we came across one particular family in Sweden. We had five tumor samples from this one family, and all showed a deletion of a specific region on chromosome 13. That gave us a hint that something was going on in this chromosomal region. So, we followed up the tumor studies by analyzing corresponding blood samples for distinct markers in the deleted region on chromosome 13, and found that all affected individuals in this family shared a common haplotype, or stretch of DNA, in a region of chromosome 13 called 13q21-22. Analysis of additional families, who did not have mutations in either BRCA1 or BRCA2, gave further evidence that these markers were linked to breast cancer susceptibility in some families, but not in others.
One advantage of doing this kind of study in Scandinavian countries is that we have good family data to work with in our population registries, which lets us trace families back and figure out pedigrees. Also, we have very good cancer registries to follow up on. The other advantage in doing these studies in Scandinavia is that the populations are fairly homogeneous, meaning that they share many common genes that might be harder to detect in a more mixed or heterogeneous population.
Answered by: Dr. Heli Nevanlinna, geneticist, Helsinki University Central Hospital, Finland:
The importance of the families in the research was crucial. The patients and their families have been very helpful and have participated well in the study. The families were recruited by interviewing breast cancer patients and finding those with several family members who have been affected by breast cancer.
This work really dates back several years, when we first recruited these families. At that time, not much was known about hereditary breast cancer, so the families were very eager to participate in the research. Since then, two genes have been discovered, BRCA1 and BRCA2. But still, there was a very large fraction of hereditary breast cancer cases that couldn't be explained by these two genes. So, we continued looking for other genes that might be involved.
Answered by: Dr. Rosa Bjork Barkardottir, molecular biologist, University Hospital of Iceland:
The collaboration was very important, particularly the part that the NHGRI played. Also, the grants we received from the Nordic Cancer Society were especially helpful in making it possible for all the groups to collaborate.
Putting the tumor and family data together from all three countries - Finland, Sweden and Iceland - was the main reason for being able to detect this candidate region for a possible new breast cancer susceptibility gene. But we really need to extend our material and collect more families to confirm our findings. It is very important to have groups in countries other than Finland, Sweden and Iceland to confirm this as well.
Answered by: Dr. Tommi Kainu, former researcher, NHGRI:
While genetic susceptibility may account for only up to roughly a third of all breast cancers, every breast cancer is caused by genetic changes. These changes occur in the tumor cells themselves, and each tumor cell accumulates these genetic changes as the disease progresses.
The long-standing theory, going back to the 1970s, is that to a large extent, cancers are caused by a loss of function of tumor suppressor genes - genes that, when active, are able to suppress the formation of tumors. In hereditary cancers, according to this so-called "two-hit" theory, you have a mutated copy of a gene on one chromosome, inherited from either your mother or your father. And then, because of some "hit," or environmental event, you lose the other copy of the gene on the other chromosome. This event spurs the initiation of cancer, since there is no good copy of the gene left to balance out the inherited bad one. This also explains why some people are so susceptible to certain types of cancer because they need only one hit on one chromosome, whereas a "normal" person would need two hits on the same region of both chromosomes.
Answered by: Dr. Olli Kallioniemi, former senior investigator, NHGRI:
When scientists look at a sample of tumor tissue taken from a patient who has undergone surgery for breast cancer, they have a one-time snapshot into the entire development process of the cancer. The cancer has probably been developing for five, 10, maybe 15 years, before it actually becomes clinically detectable. So the challenge is to understand what is the cause and what is the consequence of this lengthy process.
Trying to find out what causes cancer to progress is like piecing together the cause of an airplane crash after the fact. Just as one small mechanical defect in the airplane can lead to a crash, one tiny genetic alteration can set off the entire cancer process. When a tumor starts to develop, it is as chaotic in terms of what happens to the genome as when a plane crashes on the ground. There's a complete screw-up of the genome in the cells that have become cancerous. And trying to find the cause of the early genetic alterations that put the cancer process in motion is just as challenging as sifting through the wreckage of an airplane for the defect that caused the crash.
Answered by: Dr. Tommi Kainu, former researcher, NHGRI:
Comparative genomic hybridization is a technique that shows which regions in the genome are amplified, meaning that more copies of genes occur in the tumor cells than do in normal cells, or that one or both copies of certain genes have been lost in the tumor cells.
In comparative genomic hybridization, or CGH, you place normal chromosomes on a slide. And then you take equal amounts of DNA from two sources - DNA from cancer cells and DNA from normal human cells. These two DNA sources are labeled in different colors - red and green, for example. When the labeled DNA sources are hybridized, or joined, to the normal chromosomes on the slide, more or less of each type of DNA will hybridize to the chromosomes, depending on the relative amounts of tumor or normal DNA in the mixture.
Proc. Natl. Acad. Sci. USA, Vol. 97, Issue 17, 9603-9608, August 15, 2000
Last Reviewed: February 27, 2012