BioWorld International Correspondent

LONDON Hopes that scientists had identified a third gene responsible for many cases of familial breast cancer named the BRCA3 gene have weakened, following the failure of an international consortium of researchers to substantiate the finding.

The original report, in August 2000, by a team working in Finland, Iceland and Sweden, together with scientists at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health in Bethesda, Md., indicated that inheritance of the part of chromosome 13 known as 13q21 was linked to development of breast cancer in a group of Nordic families.

Now, however, members of the international Breast Cancer Linkage Consortium (BCLC) have reported in the Jan. 22, 2002, issue of Proceedings of the National Academy of Sciences (PNAS) that they failed to find any link with this genetic locus. The title of the paper is: “Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple-case families from the Breast Cancer Linkage Consortium.”

Andy Futreal, senior team leader in the Cancer Genome Project at the Wellcome Trust Sanger Centre in Hinxton, UK, and one of the authors of the paper, told BioWorld International: “The original study may be correct, but our goal was to assess the contribution of the locus in the set of families that we work with, and we showed there was no evidence linking inheritance of this locus with development of breast cancer in this family set. In fact, there was quite strong evidence against linkage.”

The BCLC looked for markers in the area known as 13q21 in 650 women belonging to 128 families with at least three members who had been diagnosed with breast cancer before the age of 60. The families were from Europe (the United Kingdom, Germany, Spain, the Netherlands and France), the United States, Australia, Israel and Canada, with one family from Mexico. At least one affected member from each family was first tested to ensure that no mutations in BRCA1 or BRCA2 were present.

The results, the BCLC reported, “clearly conflict” with those reported earlier in the August 2000 paper by Kainu et al., which were published in the Aug. 15, 2000, issue of PNAS. For this study, the researchers analyzed members of 77 Finnish, Icelandic and Swedish breast cancer families who had none of the known mutations in BRCA1 and BRCA2. They found that family members with breast cancer were significantly more likely to have inherited 13q21 than those who had not developed breast cancer.

Olli Kallioniemi, of the Cancer Genetics Branch of the NHGRI and one of the authors of the August 2000 paper, told BioWorld International that the paper by the BCLC was an important follow-up study. “It indicates, however, that in their family material, linkage to 13q21 does not appear to be as important as in our earlier study,” he said.

There also were important differences between the two studies in their design and in the families who took part, Kallioniemi added, which meant further investigations would be required before definitive conclusions could be drawn. “In fact, our recent results, which will soon be published, are entirely consistent with those reported by the BCLC,” he said. “We also find no evidence for 13q21 linkage among the early age of onset families. Virtually all evidence of linkage in our material came from families that did not meet the inclusion criteria for this BCLC study. Furthermore, most of the evidence for linkage came from the Finnish population, which is relatively isolated, has often been reported to display a different spectrum of disease gene mutations than other populations, and has a very small fraction of breast cancer families attributable to the previously isolated BRCA1 gene.”

The final answer on whether a gene exists at 13q21 that contributes to hereditary cases of breast cancer will not come from linkage analysis, he said, but from isolating the gene and searching for mutations within it, among affected families.

Futreal said there were two possible explanations for the discrepancy in the findings. “One is that the Finnish linkage is incorrect,” he said. “The other would attribute the discrepancy to substantial genetic heterogeneity in the different study populations, assuming a much higher frequency of disease alleles for this one locus in the former study.”

The BCLC is planning to continue its work with families affected by breast cancer who are negative for mutations in BRCA1 and BRCA2, to try to identify further genetic loci that are inherited by those family members who develop breast cancer. “It’s clear from the work that has been done so far that there is unlikely to be a single BRCA3 locus that makes up the rest of the families that do not have mutations in BRCA1 and BRCA2,” Futreal said. “It’s much more likely that there will be BRCA3, BRCA4, BRCA5, BRCA6 and BRCA7 or some similar scenario.”