THE BREAST CANCER LINKAGE CONSORTIUM
past, present & future

The Breast Cancer Linkage Consortium (BCLC) is a worldwide cooperative network of scientist who share a major interest in inherited breast and ovarian cancer. By means of annual workshop meetings and collating information contributed by the participating centres, the most salient accomplishments of the BCLC are the estimates of genetic heterogeneity of inherited breast cancer and of the cumulative cancer risks conferred by the breast cancer genes BRCA1 and BRCA2, and the characterization of the histopathological features of breast tumors arising in BRCA1 or BRCA2 carriers. The BCLC database currently holds genetic data on over 700 breast cancer families from Europe, Canada, and USA. The number of different centres involved in the BCLC is approximately 100.

CONTENTS


Kicking off...

The BCLC was founded in 1989 in Lyon, France, where a small group of scientists met in November that year to discuss opportunities to find breast cancer predisposition genes by linkage analysis in families with multiple cases of breast cancer. In 1990, the infrastructure to share linkage information was created, and the first joint analyses were performed on marker data from chromosome 1.

BRCA1....

A decisive impetus to this initiative was provided by the report of Mary-Claire King's group, at the American Society of Human Genetics Meeting in the fall of 1990, claiming genetic linkage with markers for chromosome 17 in 7 families with early-onset breast cancer. During the precipitating series of densely spaced meetings, the BCLC collected information on 214 families, consistently typed for a set of markers flanking the BRCA1 locus. The results not only overwhelmingly confirmed the BRCA1 locus on 17q, but also positioned it firmly between a number of polymorphic markers. But most importantly, it decisively showed that BRCA1 was particularly associated with families in which both breast and ovarian cancer occur frequently. This study also provided conclusive evidence that other breast cancer genes had to exist, as only 45% of all breast cancer-only families could be explained by BRCA1. The Consortium then went on to estimate cumulative breast and ovarian cancer risks conferred by mutations in BRCA1, and the results of this study were published in 1994.

And BRCA2....

Because the Consortium rapidly grew bigger in terms of groups involved, the opportunities for more individual collaborations grew accordingly. Mike Stratton's group in London, UK, teamed up with several other BCLC-groups to show that families with a case of male breast cancer were particularly unlikely to be due to BRCA1. Even though such families are rare, this collaboration was able to analyse a sufficient number of such families to detect, by linkage analysis, the second breast cancer gene on chromosome 13. These results were published in the fall of 1994, a week before the identification of BRCA1 by a team of researchers, led by Mark Skolnick, from the University of Utah and Myriad Genetics.

Mutation testing

The identification of BRCA1, and shortly thereafter of BRCA2, meant yet another boost to the ever growing number of research groups that are participating in the Consortium, because many centres started to type and find mutations in these genes, and became interested in joining the studies of the Consortium, and sharing with it their valuable information. This then enabled a more detailed analysis of the contributions of BRCA1 and BRCA2 to multiple case breast and/or ovarian cancer families, further dissecting the genetic heterogeneity of this hereditary cancer syndrome. The results showed that BRCA1 and BRCA2 typically confer high risks to breast and ovarian cancer, and accordingly together explain almost all families with 6 or more cases of breast cancer diagnosed under 60, almost all breast-ovarian cancer families, and almost all families with at least one case of male breast cancer. It also showed that other genes remain to be identified, particularly in the group of breast cancer-only families with 4-5 cases of breast cancer.

Pathology

The growing number of families with a proven BRCA1 or BRCA2 mutation also enabled to investigate, more accurately than previously done by others, whether or not inherited breast cancer is a different entity relative to sporadic breast cancer. Collating histology and pathology data on almost 200 cases, the BCLC showed that, indeed, breast cancer developing in BRCA1/2 carriers is generally of higher grade. Atypical medullary carcinoma is more frequent among BRCA1 cancers, while, unexpectedly, DCIS was found less frequently.

European support

In 1993, 25 European groups participating in the BCLC formed a concerted action under the Fourth Framework Biomed1 programme of the European Commission. This concerted action covered meeting costs, as well as costs to set up and maintain the infrastructure and databases of the BCLC. The participants had their travel expenses, incurring to attend the BCLC-meetings, refunded by this program. This concerted action got a sequel under the Biomed2 programme, with 35 contractors, which will run until December 1998. As a result, the meetings were consistently organized in Europe, and the attendees are a mixed bag of those supported by the EC, and those that are not. The EC- project greatly stimulated the activities within the group, but it also accelerated the transformation of the initial "small workshop-format" meetings into a more major annual happening (the last 3 meetings had approximately 125 participants), although the "informal" character of it remained.

Future of the BCLC

With the identification of BRCA1 and BRCA2, the questions that were being addressed by the BCLC diversified rapidly, extending into clinical, pathological, and more fundamental genetic research. This process is still ongoing, as can be judged from the studies that are currently being undertaken by the BCLC. Much more work remains to be done, however, and the method of concertation will continue to be a powerful means, if in some cases not the only means, by which to provide definitive answers to many of these questions. The "L" in the acronym BCLC will surely meet with competition from other methods as a factor providing the strongest incentive for the group to stick together, although for some targets, such as the detection of BRCA3, the BCLC will continue to do what it did best. For one thing, the database which has been constructed to date will remain a powerful resource to design new studies on it, in particular if it can be followed-up longitudinally. Regardless of the funding situation therefore, the opportunities for further collaborative networking are very good.

Joining the BCLC

The BCLC is an open data-sharing platform which can be joined by anybody who has research interests in this field and wishes to contribute the information generated in their Institute to a large international data set. The calls for specific sets of data are distributed to all participants currently on our mailing list, and any group who feels they have meaningful information to contribute can specifically enter that particular study. Participating in the BCLC by no means implies that one is obliged to contribute to all ongoing studies, nor does it mean that the data that are being contributed cannot be published elsewhere (simultaneously or earlier). In general, however, many groups have shared bits of data that would be have been difficult to be published in a stand-alone paper, but in this way could still make it to press. Hence small and not so well equipped research groups have had the opportunity to contribute their data to the total data set, making that set more powerful analytically speaking. In return this gave them the advantage of being able to access it for their own scientific ventures. Although many of the present studies are being developed and monitored from within the BCLC Steering Group, any participating centre can initiate a joint study and launch a data call.
The BCLC secretariat now has two types of participants on the mailing list. The majority regularly contribute to studies of the BCLC, and about two-thirds of those are being supported by the EC. The rest are in the process of starting up comparable research lines, or are affiliated with clinical departments that might allow them in the near future to contribute. They will also receive all data calls, be informed about the meetings, and be given the opportunity to join those meetings.

Meetings held by the BCLC

General Meetings:

  1. November 1989 - Founding meeting in Lyon, France
  2. November 1990 - Lyon, France
  3. April 1991 - Edinburgh, United Kingdom
  4. October 1991 - London, United Kingdom
  5. June 1992 - Leiden, The Netherlands
  6. May 1993 - Manchester, United Kingdom
  7. May 1994 - Paris, France
  8. February 1995 - Lillehammer, Norway
  9. December 1995 - Heidelberg, Germany
  10. October 1996 - Lyon, France
  11. September 1997 - Pisa, Italy
  12. September 1998 - Dublin, Ireland

Task Force Meetings:

  1. June 1997 - Leiden, The Netherlands
  2. October 1997 - Clermont-Ferrand, France
  3. April 1998 - Noordwijk, The Netherlands
  4. April 1999 - Lyon, France

The BCLC Steering Group

When the BCLC started receiving support from the European Commission, there was a need to install a project management team, in order to coordinate the studies outlined in the EC-project proposal and their annual assessment. For this reason the Steering Group consists of individuals intimately involved in the final (statistical) analysis of collated datasets. As a consequence, many new studies are presently also discussed and developed within this group, even though any person can approach members of the BCLC with a proposal for a joint study. However, some central clearance of studies is desirable to avoid duplication and conflicts of interests. The SG therefore strongly adheres to being informed about a study-proposal prior to its circulation among the BCLC members.


Last update: 10 jun 1999