Clinical implications of gene dosage and gene expression patterns in diploid breast carcinoma.
OBJECTIVE
Deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells. In cancer, regulation of gene transcription can be mediated in a variety of ways. The purpose of this study was to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels, and to associate these genomic changes with clinicopathologic parameters.


METHODS
We screened 97 invasive diploid breast tumors for DNA copy number alterations and changes in transcriptional levels using array comparative genomic hybridization and expression microarrays, respectively.


RESULTS
The integrative analysis identified an increase in the overall number of genetic alterations during tumor progression and 15 specific genomic regions with aberrant DNA copy numbers in at least 25% of the patient population, i.e., 1q22, 1q22-q23.1, 1q25.3, 1q32.1, 1q32.1-q32.2, 8q21.2-q21.3, 8q22.3, 8q24.3, and 16p11.2 were recurrently gained, whereas 11q25, 16q21, 16q23.3, and 17p12 were frequently lost (P < 0.01). An examination of the expression patterns of genes mapping within the detected genetic aberrations identified 47 unique genes and 1 Unigene cluster significantly correlated between the DNA and relative mRNA levels. In addition, more malignant tumors with normal gene dosage levels displayed a recurrent overexpression of UBE2C, S100A8, and CBX2, and downregulation of LOC389033, STC2, DNALI1, SCUBE2, NME5, SUSD3, SERPINA11, AZGP1, and PIP.


CONCLUSIONS
Taken together, our findings suggest that the dysregulated genes identified here are critical for breast cancer initiation and progression, and could be used as novel therapeutic targets for drug development to complement classical clinicopathologic features.
Parris
Toshima Z
TZ
Department of Oncology, Institute of Clinical Sciences, and Laboratory of Clinical Pathology and Cytology, Sahlgrenska Academy at University of Gothenburg, Gula stråket 2, Gothenburg, Sweden. toshima.parris@oncology.gu.se
Danielsson
Anna
A
Nemes
Szilárd
S
Kovács
Anikó
A
Delle
Ulla
U
Fallenius
Ghita
G
Möllerström
Elin
E
Karlsson
Per
P
Helou
Khalil
K
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002469:Cell Separation; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D004171:Diploidy; D005260:Female; D005434:Flow Cytometry; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction