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No evidence for a familial breast cancer susceptibility gene at chromosome 13q21 in Swedish breast cancer families

Dear Sir, To date, 2 major breast cancer and/or ovarian cancer predisposition genes have been identified. However, a significant proportion of families with multiple cases of breast cancer cannot be explained by mutations in the BRCA1 and BRCA2 genes,1 especially in the Nordic populations.2–4 In addition, epidemiologic studies suggest that, in contrast to many other populations, breast cancer families recruited from the Stockholm region were not characterized by early onset and bilateral disease.5 It was proposed that additional breast cancer susceptibility genes may account for some of high-risk families in this region. Based on comparative genome hybridization (CGH) data and targeted linkage analysis, Kainu et al.6 recently suggested 13q21 as a putative novel breast cancer susceptibility locus in the Nordic populations. We have evaluated the potential contribution of this putative locus to breast cancer susceptibility in 96 Stockholm families without detected BRCA1 and BRCA2 mutations. The linkage analysis yielded an overall multipoint lod score of 49.47 at marker D13S1308, which was suggested to be the BRCA3 locus. The result does not support the hypothesis that chromosome 13q21 harbors a familial breast cancer susceptibility gene that plays a role in Swedish breast cancer families. High-risk breast cancer families were identified and collected through the cancer counseling clinics in the Stockholm region. Families including at least 2 firstor second-degree relatives with only female breast cancer were used in our study, with no age limitation. Twenty of these families have 2 affected cases, 42 families have 3 cases, 24 families have 4 cases, 8 families have 5 cases and 2 families have 6 cases, with an average of 3.2 cases per family. The average age at diagnosis of these patients is 54.7 years old, with a range of 30–72 years. No other types of cancer were presented in this set of families. Blood samples were obtained from the affected and unaffected family members with informed consent. To evaluate the contribution of chromosome 13q21 to familial breast cancer predisposition, we performed linkage analysis with microsatellite markers spanning chromosome 13, as well as the BRCA1 locus of chromosome 17, in families without identified BRCA1 and BRCA2 mutations. Linkage analysis involved 272 members from 96 breast cancer families, including 232 breast cancer patients. Of these families, 61 families have 2 typed patients, 30 families have 3 typed patients, 4 families have 4 typed patients and 1 family has 5 typed patients. Exclusions of exon 11 of BRCA1 was performed by protein truncation test (PTT) and other exons of BRCA1 were excluded by constant denaturing gel electrophoresis (CDGE) and single-stranded conformation polymorphism analysis (SSCP). The exclusions of exon 10 and 11 of BRCA2 were performed by PTT on genomic DNA and other exons were excluded by PTT on RNA. Later on, exclusion of BRCA1 and BRCA2 was performed by direct sequencing for all exons.2–4 Genotyping data were first checked for consistency by using PEDCHECK.7 Homozygosity tests were performed to further check marker quality and typing errors. Model-dependent multipoint lod scores were generated by using the GENEHUNTER 2.1 program,8 complemented by LINKMAP of the FASTLINK program.9,10 Two-point lod scores were performed by using the MLINK of the FASTLINK package because multipoint lod scores are always affected by flanking markers and marker density. We assigned an autosomal dominant inheritance model in the linkage analysis, with only female breast cancer as the phenotype. The gene frequency was set to 0.003. Agedependent penetrance for carriers was used. The penetrance was set to 0.01 for unaffected males, 0.20 for unaffected females below 40 years old, 0.40 for unaffected females between 40–65 years old and 0.6 for unaffected female above 65 years old. Marker allele frequencies were estimated by PEDCHECK from individuals in each pedigree. Published map distances from Marshfield (http://research.marshfieldclinic.org) were used in the analysis. The overall lod scores were maximized to allow for heterogeneity (Hlod). At each locus a maximum Hlod and a corresponding estimate of the proportion of families linked ( ) were obtained. Most of these families showed some evidence against linkage to BRCA1 and BRCA2. Combined multipoint lod scores are shown in Table I. The overall multipoint lod scores were strongly negative across all of chromosome 13. Of the 102 families, 73 families generated negative multipoint lod scores, and only 29 families were positive at marker D13S1308, with the highest lod score of 0.83 in family 4046. Compared with flanking regions of chromosome 13 and BRCA1 locus (Table II), the putative locus has a more negative lod score. This is not