Influence of whole arm loss of chromosome 16q on gene expression patterns in oestrogen receptor-positive, invasive breast cancer.

TY - JOUR

T1 - Influence of whole arm loss of chromosome 16q on gene expression patterns in oestrogen receptor-positive, invasive breast cancer.

AU - Hungermann, Daniela

AU - Schmidt, Hartmut

AU - Natrajan, Rachel

AU - Tidow, Nicola

AU - Poos, Kathrin

AU - Reis-Filho, Jorge S

AU - Brandt, Burkhard

AU - Buerger, Horst

AU - Korsching, Eberhard

PY - 2011

Y1 - 2011

N2 - A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis.

AB - A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis.

KW - Humans

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Dosage

KW - Neoplasm Invasiveness

KW - Breast Neoplasms/genetics/metabolism/pathology

KW - Carcinoma, Ductal, Breast/genetics/metabolism/pathology

KW - Chromosome Deletion

KW - Chromosomes, Human, Pair 16/genetics

KW - Comparative Genomic Hybridization/methods

KW - Gene Expression Profiling/methods

KW - Neoplasm Proteins/metabolism

KW - Oligonucleotide Array Sequence Analysis/methods

KW - Receptors, Estrogen/metabolism

KW - Reverse Transcriptase Polymerase Chain Reaction/methods

KW - Humans

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Dosage

KW - Neoplasm Invasiveness

KW - Breast Neoplasms/genetics/metabolism/pathology

KW - Carcinoma, Ductal, Breast/genetics/metabolism/pathology

KW - Chromosome Deletion

KW - Chromosomes, Human, Pair 16/genetics

KW - Comparative Genomic Hybridization/methods

KW - Gene Expression Profiling/methods

KW - Neoplasm Proteins/metabolism

KW - Oligonucleotide Array Sequence Analysis/methods

KW - Receptors, Estrogen/metabolism

KW - Reverse Transcriptase Polymerase Chain Reaction/methods

M3 - SCORING: Journal article

VL - 224

SP - 517

EP - 528

JO - J PATHOL

JF - J PATHOL

SN - 0022-3417

IS - 4

M1 - 4

ER -