title: BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays.
abstract: A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.
authors.affiliation: Department of Pathology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario, Canada.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Bane
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Beck
authors.forename: Ira
authors.initials: I
authors.lastname: Bleiweiss
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.forename: Edison
authors.initials: E
authors.lastname: Catalano
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Graham
authors.initials: G
authors.lastname: Giles
authors.forename: Andy K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Lester
authors.initials: L
authors.lastname: Layfield
authors.forename: Teri
authors.initials: T
authors.lastname: Longacre
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Rubie
authors.initials: R
authors.lastname: Senie
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Dee W
authors.initials: DW
authors.lastname: West
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Frances P
authors.initials: FP
authors.lastname: O'Malley
mesh_terms: D000328:Adult; D000368:Aged; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D006801:Humans; D053555:Keratin-5 / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D053555:Keratin-5; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D044767:Ubiquitin-Protein Ligases; C111164:BRAP protein, human