BCLC-study: Characterization of the haplotypes of recurrent BRCA1 and BRCA2 mutations of diverse geographical origin

Coordinators Teresa Wagner (Vienna, Austria); Csilla Szabo (Lyon, France)
Aim To estimate the age of the mutations, derive a phylogenetic tree of haplotype alterations, and correlate this information with ethnic and geographic information provided on the families.
Calls for DNA samples of carriers. Two centers will be performing the genotypings of polymorphic markers to ensure correct and consistent calling of allele-lengths.
Status The first batch of samples has been received, and genotyping will start in July 1999. An update of the number of samples received to date can be found here for BRCA1 and BRCA2.


During the recent EU Breast Cancer Linkage Consortium meeting in Dublin we described in broad outlines an ongoing study on the haplotypes associated with BRCA1 mutations that have been identified in multiple independent families of diverse origins. We would like to invite you to participate in these studies on a collaborative basis.

Background and Objectives of the Collaboration

Identification of BRCA1 and BRCA2 and subsequent characterization of mutations in these genes revealed that, while the majority of mutations are unique, several are found in multiple families. Frequently described mutations appear to be population-specific (e.g. the 2804delAA in the Netherlands), or, in some instances (e.g. the 5382insC) occur in geographically and ethnically diverse families (reviewed in Szabo and King, 1997). Many of you may have participated in the initial collaborative studies coordinated by Susan Neuhausen and David Goldgar that were designed to investigate the haplotypes associated with these mutations (Neuhausen et al., 1996; Neuhausen et al., 1998).

The goal of the present collaborative study is to augment the previous studies with data from a broader series of mutation carriers, and to characterize additional mutations for which enough occurrences have now been reported to permit a detailed analysis of the associated haplotypes. Incorporation of additional markers will allow for finer resolution mapping of haplotypes over a longer distance than in the previous studies. For each mutation to be studied, we will estimate the age of the mutation, derive a phylogenetic tree of haplotype alterations, and correlate this information with ethnic and geographic information provided on the families. In this manner we hope to characterize the spread of these mutations from their place of origin to other regions of Europe, and the relevant populations in the United States, Canada and Australia. Initial analysis will focus on BRCA1 mutations, as it is anticipated that accumulation of a sufficient number of families with frequent BRCA2 mutations to conduct these analyses may take some time.

Eligibility criteria

1. Any family identified with any of the following mutations (reported >10 times in families from 2 or more countries in Europe):

Gene Mutations
BRCA1 185delAG; Cys61Gly; Intron 5 T>G + ins59; 1135insA; 1294del40; 1806 C>T; 2080delA; Q563X; Q780X; 3600del11; 3604delA; 3875del4; 4184del4; E1250X; Q1395X; R1443X; 5382insC; R1835X
BRCA2 2041insA; 2157delG; 3034del4; 6174delT; 6503delTT; 9326insA; K3326X

Collaborations on population-specific mutations are also welcome.

2. Being able to provide us with 10 micrograms of DNA from a sufficient number of family members to establish a definitive haplotype (mutation carriers that are mother-daughter, sib-, aunt-niece, cousin-pairs, etc. are suitable); samples from single probands will also be accepted for specific mutations.

3. Information on the ethnic and geographic origin(s) of each family would be extremely useful for determining mutation origin, and relatedness between different populations.


Following the model of recent BCLC papers, resulting publications will be authored by:


If you wish to participate, please contact the organizing group (see below), detailing the number of eligible families available for each of the listed mutations. We will then contact you with further details on sample requirements and shipment. The laboratories in Vienna and Salt Lake City will perform the necessary genotypings for 17q- and 13q-markers, respectively. The statistical analyses and central coordination will be done by the Lyon center. The deadline for receipt of samples to be included in the analysis is February 1, 1999.

The Breast Cancer Gene Mutation Haplotype Collaborative Study Coordinators,

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Last updated: May 5, 1999