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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

Detection of allelic imbalance in a HER2+ breast tumor with fluorescence-based genotyping. Alleles for marker D17S250 on chromosome 17q12 were detected as fluorescent peaks in reference DNA (top panel) and microdissected breast tumor DNA (bottom panel). A normalized peak height ratio of 0.28 was calculated for the tumor sample using the following peak heights in relative fluorescence units (rfu): tumor DNA – 8,791 rfu and 30,585 rfu, referent DNA – 61,195 rfu and 59,934 rfu.
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Figure 2: Detection of allelic imbalance in a HER2+ breast tumor with fluorescence-based genotyping. Alleles for marker D17S250 on chromosome 17q12 were detected as fluorescent peaks in reference DNA (top panel) and microdissected breast tumor DNA (bottom panel). A normalized peak height ratio of 0.28 was calculated for the tumor sample using the following peak heights in relative fluorescence units (rfu): tumor DNA – 8,791 rfu and 30,585 rfu, referent DNA – 61,195 rfu and 59,934 rfu.

Mentions: Microsatellite markers were amplified as previously described [20], purified using Sephadex G-50 resin and genotyped on a MegaBACE-1000 capillary electrophoresis apparatus (Amersham Biosciences, Piscataway, NJ) following standard protocols. Genotypes were determined using Genetic Profiler version 2.0 software. AI was detected as previously described [21] using a cutoff value of 0.35 (Figure 2), which provides >80% reproducibility when AI events are confirmed on a second aliquot of DNA [22].


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)

Detection of allelic imbalance in a HER2+ breast tumor with fluorescence-based genotyping. Alleles for marker D17S250 on chromosome 17q12 were detected as fluorescent peaks in reference DNA (top panel) and microdissected breast tumor DNA (bottom panel). A normalized peak height ratio of 0.28 was calculated for the tumor sample using the following peak heights in relative fluorescence units (rfu): tumor DNA – 8,791 rfu and 30,585 rfu, referent DNA – 61,195 rfu and 59,934 rfu.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Detection of allelic imbalance in a HER2+ breast tumor with fluorescence-based genotyping. Alleles for marker D17S250 on chromosome 17q12 were detected as fluorescent peaks in reference DNA (top panel) and microdissected breast tumor DNA (bottom panel). A normalized peak height ratio of 0.28 was calculated for the tumor sample using the following peak heights in relative fluorescence units (rfu): tumor DNA – 8,791 rfu and 30,585 rfu, referent DNA – 61,195 rfu and 59,934 rfu.
Mentions: Microsatellite markers were amplified as previously described [20], purified using Sephadex G-50 resin and genotyped on a MegaBACE-1000 capillary electrophoresis apparatus (Amersham Biosciences, Piscataway, NJ) following standard protocols. Genotypes were determined using Genetic Profiler version 2.0 software. AI was detected as previously described [21] using a cutoff value of 0.35 (Figure 2), which provides >80% reproducibility when AI events are confirmed on a second aliquot of DNA [22].

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