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Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast
Author(s) -
Liao Shaoxi,
Desouki Mohamed M.,
Gaile Daniel P.,
Shepherd Lori,
Nowak Norma J.,
Conroy Jeffrey,
Barry William T.,
Geradts Joseph
Publication year - 2012
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.21991
Subject(s) - biology , ductal carcinoma , bacterial artificial chromosome , comparative genomic hybridization , chromosome , carcinoma , candidate gene , copy number variation , carcinoma in situ , gene , fluorescence in situ hybridization , breast cancer , cancer research , pathology , genetics , cancer , genome , medicine
Abstract Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low‐grade ductal carcinoma in situ (DCIS). Fifty‐five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty‐one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high‐density bacterial artificial chromosome arrays. Array comparative genomic hybridization analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases, 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples. PD cases had a higher frequency of DNA copy number changes than MD cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A , and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1 , and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multigene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas. © 2012 Wiley Periodicals, Inc.