Tiling path genomic profiling of grade 3 invasive ductal breast cancers.
OBJECTIVE
To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes.


METHODS
Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs.


RESULTS
We show that basal-like and HER-2 tumors are characterized by "sawtooth" and "firestorm" genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification.


CONCLUSIONS
Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.
Natrajan
Rachael
R
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Lambros
Maryou B
MB
Rodríguez-Pinilla
Socorro María
SM
Moreno-Bueno
Gema
G
Tan
David S P
DS
Marchió
Caterina
C
Vatcheva
Radost
R
Rayter
Sydonia
S
Mahler-Araujo
Betania
B
Fulford
Laura G
LG
Hungermann
Daniela
D
Mackay
Alan
A
Grigoriadis
Anita
A
Fenwick
Kerry
K
Tamber
Narinder
N
Hardisson
David
D
Tutt
Andrew
A
Palacios
Jose
J
Lord
Christopher J
CJ
Buerger
Horst
H
Ashworth
Alan
A
Reis-Filho
Jorge S
JS