Scientists Pinpoint Location of Possible Third Gene Involved in Hereditary Breast Cancer to Chromosome 13

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. (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.

Co-authors

Five groups totaling 35 scientists, representing 14 laboratories at eight institutions in five countries, contributed to the paper titled, “Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus,” published in the Aug. 15, 2000 issue of the Proceedings of the National Academy of Sciences. Here is a list of all the co-authors and their institutions:

Group 1: Tommi Kainu¹, Suh-Hang Hank Juo², Richard Desper³, Alejandro A. Schäffer⁴, Elizabeth Gillanders¹, Ester Rozenblum¹, Diana Freas-Lutz¹, Don Weaver¹, Dietrich Stephan¹, Joan Bailey-Wilson², and Olli-P. Kallioniemi¹.

1. Cancer Genetics Branch, NHGRI, NIH, Bethesda, MD, USA. 2. Inherited Disease Research Branch, NHGRI, NIH, Baltimore, MD, USA. 3. Abteilung Theoretische Bioinformatik, Deutsches Krebsforschungzentrum (DKFZ), Heidelberg, Germany. 4. Computational Biology Branch, National Center for Biotechnology Information, NIH, Bethesda, MD, USA.

Group 2: Mika Tirkkonen*¹, Kirsi Syrjäkoski¹, Tuula Kuukasjärvi², Pasi Koivisto¹, Ritva Karhu¹, and Kaija Holli³.

1. Laboratory of Cancer Genetics, 2. Department of Pathology, and 3. Department of Oncology, Tampere University and University Hospital, Finland.

Group 3: Adalgeir Arason*, Gudrun Johannesdottir, Jon Thor Bergthorsson, Hrefna Johannsdottir, Valgardur Egilsson, and Rosa Björk Bardardottir. Laboratory of Cell Biology, Department of Pathology, University Hospital of Iceland, Reykjavik, Iceland.

Group 4: Oskar Johannsson*¹, Karin Haraldsson¹, Therese Sandberg¹, Eva Holmberg³, Henrik Grönberg³, Håkan Olsson¹, and Åke Borg¹.

1. Department of Oncology, University Hospital, Lund, Sweden; 2. Department of Clinical Genetics and 3. Department of Oncology, University Hospital, Umeå, Sweden.

Group 5: Paula Vehmanen*¹, Hannaleena Eerola², Päivi Heikkilä³, Seppo Pyrhönen⁴, and Heli Nevanlinna.

1. Department of Obstetrics and Gynaecology, 2. Department of Oncology, and 3. Department of Pathology, Helsinki University Central Hospital, Finland. 4. Department of Oncology and Radiotherapy, Turku University Hospital, Finland.

* contributed equally to this work

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