title: Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families.
abstract: The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 individuals belonging to 30 multiple-case families; BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.
authors.affiliation: Translational Oncology, Sydney West Area Health Service, Sydney, Australia. rosemary_balleine@wmi.usyd.edu.au
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Balleine
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Provan
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Nirmala
authors.initials: N
authors.lastname: Pathmanathan
authors.forename: Margaret
authors.initials: M
authors.lastname: Cummings
authors.forename: Gelareh
authors.initials: G
authors.lastname: Farshid
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Salisbury
authors.forename: A Michael
authors.initials: AM
authors.lastname: Bilous
authors.forename: Karen
authors.initials: K
authors.lastname: Byth
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D005192:Family Health; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D012306:Risk; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D051497:Receptor, Fibroblast Growth Factor, Type 2