title: Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers.
abstract: Gene expression array profiles identify subclasses of breast cancers with different clinical outcomes and different molecular features. The present study attempted to correlate genomic alterations (loss of heterozygosity; LOH) with subclasses of breast cancers having distinct gene expression signatures. Hierarchical clustering of expression array data from 89 invasive breast cancers identified four major expression subclasses. Thirty-four of these cases representative of the four subclasses were microdissected and allelotyped using genome-wide single nucleotide polymorphism detection arrays (Affymetrix, Inc.). LOH was determined by comparing tumor and normal single nucleotide polymorphism allelotypes. A newly developed statistical tool was used to determine the chromosomal regions of frequent LOH. We found that breast cancers were highly heterogeneous, with the proportion of LOH ranging widely from 0.3% to >60% of heterozygous markers. The most common sites of LOH were on 17p, 17q, 16q, 11q, and 14q, sites reported in previous LOH studies. Signature LOH events were discovered in certain expression subclasses. Unique regions of LOH on 5q and 4p marked a subclass of breast cancers with "basal-like" expression profiles, distinct from other subclasses. LOH on 1p and 16q occurred preferentially in a subclass of estrogen receptor-positive breast cancers. Finding unique LOH patterns in different groups of breast cancer, in part defined by expression signatures, adds confidence to newer schemes of molecular classification. Furthermore, exclusive association between biological subclasses and restricted LOH events provides rationale to search for targeted genes.
authors.affiliation: Departments of Surgery and Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Lin
authors.forename: Lee-Jen
authors.initials: LJ
authors.lastname: Wei
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Gabriella
authors.initials: G
authors.lastname: Lodeiro
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Harris
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: David M
authors.initials: DM
authors.lastname: Tanenbaum
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: James D
authors.initials: JD
authors.lastname: Iglehart
authors.forename: Andrea
authors.initials: A
authors.lastname: Richardson
mesh_terms: D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D009361:Neoplasm Invasiveness / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D004273:DNA, Neoplasm; D005819:Genetic Markers