Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast.
OBJECTIVE
To gain insight into genomic and transcriptomic subtypes of ductal carcinomas in situ of the breast (DCIS).


METHODS
We did a combined phenotypic and genomic analysis of a series of 57 DCIS integrated with gene expression profile analysis for 26 of the 57 cases.


RESULTS
Thirty-two DCIS exhibited a luminal phenotype; 21 were ERBB2 positive, and 4 were ERBB2/estrogen receptor (ER) negative with 1 harboring a bona fide basal-like phenotype. Based on a CGH analysis, genomic types were identified in this series of DCIS with the 1q gain/16q loss combination observed in 3 luminal DCIS, the mixed amplifier pattern including all ERBB2, 12 luminal and 2 ERBB2(-)/ER(-) DCIS, and the complex copy number alteration profile encompassing 14 luminal and 1 ERBB2(-)/ER(-) DCIS. Eight cases (8 of 57; 14%) presented a TP53 mutation, all being amplifiers. Unsupervised analysis of gene expression profiles of 26 of the 57 DCIS showed that luminal and ERBB2-amplified, ER-negative cases clustered separately. We further investigated the effect of high and low copy number changes on gene expression. Strikingly, amplicons but also low copy number changes especially on 1q, 8q, and 16q in DCIS regulated the expression of a subset of genes in a very similar way to that recently described in invasive ductal carcinomas.


CONCLUSIONS
These combined approaches show that the molecular heterogeneity of breast ductal carcinomas exists already in in situ lesions and further indicate that DCIS and invasive ductal carcinomas share genomic alterations with a similar effect on gene expression profile.
Vincent-Salomon
Anne
A
Institut Curie, Department of Tumor Biology, Paris, France.
Lucchesi
Carlo
C
Gruel
Nadège
N
Raynal
Virginie
V
Pierron
Gaëlle
G
Goudefroye
Rémi
R
Reyal
Fabien
F
Radvanyi
François
F
Salmon
Rémy
R
Thiery
Jean-Paul
JP
Sastre-Garau
Xavier
X
Sigal-Zafrani
Brigitte
B
Fourquet
Alain
A
Delattre
Olivier
O
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
D014408:Biomarkers, Tumor