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Genetic alterations in ERBB2-amplified breast carcinomas
1Laboratory of Cancer Genetics, University and University Hospital of Tampere, Finland.
Abstract:
Amplification of the ERBB2 oncogene has recently received attention as a target for antibody-based therapies and as a predictor of response to adjuvant chemotherapy. Modification of treatment strategies based on ERBB2 status has led to further interest in the genetic alterations that accompany ERBB2 gene amplification or overexpression. In this study, chromosome alterations that are associated with ERBB2 amplification were defined by comparative genomic hybridization (CGH). Additionally, fluorescence in situ hybridization (FISH) was used to validate gene amplification, and protein expression was detected immunohistochemically. ERBB2-amplified tumors as detected by FISH, immunohistochemistry (IHC), or CGH had twice as many CGH-defined chromosomal alterations (means of 11.8, 11.0, and 12.7, respectively) as the nonamplified tumors (means of 6.8, 7.0, and 5.6, respectively). ERBB2 positivity correlated with the total number of genetic events. A wide spectrum of copy number gains and losses was seen by CGH in all of the tumors. An increased number of losses of 18q and gains of 20q was found in ERBB2-positive tumors. Other common aberrations for all of the tumors were copy number gains of 1q (58%), 8q (52%), 20q (30%), and losses of 18q (39%), 13q (39%), and 3p (33%). A high degree of concordance was observed among the three methods in 33 primary breast cancers. The concurrence for ERBB2 detection between FISH and IHC was 90%, between FISH and CGH was 82%, and between IHC and CGH was 84%. This study shows that breast tumors showing erbB2 overexpression or gene amplification are genetically distinct from erbB2-negative tumors. These differences may relate to the mechanisms underlying altered response to adjuvant therapies and may define the responsiveness to erbB2-directed immunotherapy.
Insights
ERBB2 gene amplification in breast cancer is linked to more chromosomal alterations. These genetic differences may explain varied responses to therapies and predict immunotherapy effectiveness.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- ERBB2 (ErbB2) oncogene amplification is a key target for breast cancer therapies and predicts chemotherapy response.
- Understanding genetic alterations associated with ERBB2 amplification is crucial for refining treatment strategies.
Purpose of the Study:
- To define chromosome alterations associated with ERBB2 amplification in breast cancer.
- To correlate ERBB2 status with the overall number of genetic events and specific chromosomal aberrations.
- To assess the concordance of different methods for detecting ERBB2 amplification and overexpression.
Main Methods:
- Comparative Genomic Hybridization (CGH) to identify chromosomal alterations.
- Fluorescence In Situ Hybridization (FISH) to validate ERBB2 gene amplification.
- Immunohistochemistry (IHC) to detect ERBB2 protein expression.
Main Results:
- ERBB2-amplified tumors exhibited significantly more chromosomal alterations (11.8-12.7) compared to non-amplified tumors (5.6-7.0).
- ERBB2 positivity correlated with a higher total number of genetic events.
- Increased losses of 18q and gains of 20q were observed in ERBB2-positive tumors. High concordance (82-90%) was found between FISH, IHC, and CGH methods.
Conclusions:
- Breast tumors with ERBB2 overexpression or amplification are genetically distinct from ERBB2-negative tumors.
- These genetic differences may underlie altered responses to adjuvant therapies.
- The distinct genetic profile of ERBB2-positive tumors may predict responsiveness to ERBB2-directed immunotherapies.