Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families

✍ Scribed by Rosemary L. Balleine; Pamela J. Provan; Gulietta M. Pupo; Nirmala Pathmanathan; Margaret Cummings; Gelareh Farshid; Elizabeth L. Salisbury; A. Michael Bilous; Karen Byth; Graham J. Mann

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 499 KB
• Volume: 49
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20816

✦ Synopsis

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. © 2010 Wiley‐Liss, Inc.