title: Immunohistochemical classification of non-BRCA1/2 tumors identifies different groups that demonstrate the heterogeneity of BRCAX families.
abstract: Around 25% of hereditary breast and ovarian cancer families have mutations in the BRCA1 and BRCA2 genes. The search for other genes has until now failed, probably because there is not one single BRCAX gene, but rather various genes that may each be responsible for a small number of breast cancer families and/or may interact according to a polygenic model. We have studied 50 tumors from probands belonging to non-BRCA1/2 breast cancer families (BRCAX), using 25 immunohistochemical markers. The objective was to classify these tumors and confirm that they are heterogeneous. Unsupervised cluster analysis showed the existence of the following two main groups of tumors: high-grade and estrogen receptor (ER)-negative tumors (50%), and low-grade and ER-positive tumors (50%). In addition we identified five subgroups, three among the high-grade and two among the low-grade groups; one overexpressing HER-2 (18%); one with a basal-like phenotype (14%); one with a normal breast-like phenotype (18%); a luminal A subgroup (36%), and a luminal B subgroup (14%). Hypermethylation of the BRCA1 gene was observed in 42% of the cases, spread across all five subgroups, but only 37% of those had loss of heterozygosity as well. These latter cases were all clustered in the high-grade group and the majority of them in the basal-like subgroup. Our results show that familial non-BRCA1/2 tumors are heterogeneous and suggest a polygenic model for explaining the majority of BRCAX families. In addition we have defined a subset of them that have somatic inactivation of the BRCA1 gene.
authors: Department of Human Genetics, Spanish National Cancer Centre, Melchor Fernandez Almagro 3, Madrid, Spain.
authors: Emiliano
authors: E
authors: Honrado
authors: Ana
authors: A
authors: Osorio
authors: Roger L
authors: RL
authors: Milne
authors: María F
authors: MF
authors: Paz
authors: Lorenzo
authors: L
authors: Melchor
authors: Alberto
authors: A
authors: Cascón
authors: Miguel
authors: M
authors: Urioste
authors: Alicia
authors: A
authors: Cazorla
authors: Orland
authors: O
authors: Díez
authors: Enrique
authors: E
authors: Lerma
authors: Manel
authors: M
authors: Esteller
authors: José
authors: J
authors: Palacios
authors: Javier
authors: J
authors: Benítez
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics*; D016000:Cluster Analysis; D019175:DNA Methylation; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018740:Genetic Heterogeneity; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000145:classification / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D046888:Tissue Array Analysis
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen