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Amplification of HER2 is a marker for global genomic instability.

Ellsworth RE, Ellsworth DL, Patney HL, Deyarmin B, Love B, Hooke JA, Shriver CD - BMC Cancer (2008)

Bottom Line: Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer.In addition, high levels of DNA damage may render tumor cells refractory to treatment.These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Breast Care Project, Henry M, Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, USA. r.ellsworth@wriwindber.org

ABSTRACT

Background: Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer.

Methods: HER2 status was determined using the PathVysion assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n=39) or HER2 negative (n=142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status.

Results: The frequency of AI was significantly higher (P<0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P<0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21.

Conclusion: The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

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Related in: MedlinePlus

Schematic diagram of the 17q12-q21 region. Genes involved in breast cancer are listed across the top, with distance between genes noted. Patterns of AI are as follows: solid line = HER2- tumors, dotted line = HER2 amplified. Black circles represent an AI event, white circles, normal chromosomal content. Where there is no circle, the reference genotype was homozygous, and thus uninformative.
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Figure 3: Schematic diagram of the 17q12-q21 region. Genes involved in breast cancer are listed across the top, with distance between genes noted. Patterns of AI are as follows: solid line = HER2- tumors, dotted line = HER2 amplified. Black circles represent an AI event, white circles, normal chromosomal content. Where there is no circle, the reference genotype was homozygous, and thus uninformative.

Mentions: Because the HER2 gene is located within one of the 26 regions in our AI panel, patterns of AI at 17q12-q21 were examined. The two markers used to assess chromosomal content at 17q12-q21, D17S250 and D17S579, define a 5.7Mb region that includes not only the HER2 and TOP2A genes but also the signal transducer and activator of transcription 3 (STAT3) and breast cancer 1 (BRCA1) genes (Figure 3). In samples with AI at chromosome 17q12-q21, the majority of HER2- cases had AI at either D17S250 (24%) or D17S579 (59%), while in 50% of HER2+ tumors, AI was detected at both markers, suggesting that multiple genes from the 17q region may be altered in HER2+ tumors.


Amplification of HER2 is a marker for global genomic instability.

Ellsworth RE, Ellsworth DL, Patney HL, Deyarmin B, Love B, Hooke JA, Shriver CD - BMC Cancer (2008)

Schematic diagram of the 17q12-q21 region. Genes involved in breast cancer are listed across the top, with distance between genes noted. Patterns of AI are as follows: solid line = HER2- tumors, dotted line = HER2 amplified. Black circles represent an AI event, white circles, normal chromosomal content. Where there is no circle, the reference genotype was homozygous, and thus uninformative.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2571108&req=5

Figure 3: Schematic diagram of the 17q12-q21 region. Genes involved in breast cancer are listed across the top, with distance between genes noted. Patterns of AI are as follows: solid line = HER2- tumors, dotted line = HER2 amplified. Black circles represent an AI event, white circles, normal chromosomal content. Where there is no circle, the reference genotype was homozygous, and thus uninformative.
Mentions: Because the HER2 gene is located within one of the 26 regions in our AI panel, patterns of AI at 17q12-q21 were examined. The two markers used to assess chromosomal content at 17q12-q21, D17S250 and D17S579, define a 5.7Mb region that includes not only the HER2 and TOP2A genes but also the signal transducer and activator of transcription 3 (STAT3) and breast cancer 1 (BRCA1) genes (Figure 3). In samples with AI at chromosome 17q12-q21, the majority of HER2- cases had AI at either D17S250 (24%) or D17S579 (59%), while in 50% of HER2+ tumors, AI was detected at both markers, suggesting that multiple genes from the 17q region may be altered in HER2+ tumors.

Bottom Line: Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer.In addition, high levels of DNA damage may render tumor cells refractory to treatment.These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Breast Care Project, Henry M, Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, USA. r.ellsworth@wriwindber.org

ABSTRACT

Background: Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer.

Methods: HER2 status was determined using the PathVysion assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n=39) or HER2 negative (n=142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status.

Results: The frequency of AI was significantly higher (P<0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P<0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21.

Conclusion: The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

Show MeSH
Related in: MedlinePlus