Limits...
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.

Show MeSH

Related in: MedlinePlus

Images of tumors before and after laser-assisted microdissection with corresponding FISH data. The tumor specimen on the top was taken from a pre-menopausal woman with stage IIb IDCA, without amplification of the HER2 gene. The tumor specimen on the bottom was taken from a pre-menopausal woman stage IIIB IDCA and HER2 amplification of 3.3. Green signals = CEP17 probe, orange = HER2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2571108&req=5

Figure 1: Images of tumors before and after laser-assisted microdissection with corresponding FISH data. The tumor specimen on the top was taken from a pre-menopausal woman with stage IIb IDCA, without amplification of the HER2 gene. The tumor specimen on the bottom was taken from a pre-menopausal woman stage IIIB IDCA and HER2 amplification of 3.3. Green signals = CEP17 probe, orange = HER2.

Mentions: DNA was obtained from pure populations of primary breast tumor cells following laser-assisted microdissection on an AS LMD laser microdissection system (Leica Microsystems, Wetzlar, Germany) [19] (Figure 1). All microdissected sections were examined by the CBCP pathologist, who identified and marked regions of tumor before dissection. To avoid PCR artifacts, ≥ 5,000 cells were captured from each of six consecutive breast tumor sections, with the sixth section reserved for all confirmatory reruns. Referent DNA samples for the archival samples were extracted from disease-free skin or negative lymph node tissue from each patient using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA). Referent DNA for the CBCP samples was obtained from blood clots using Clotspin and Puregene DNA purification kits (Gentra, Minneapolis, MN).


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)

Images of tumors before and after laser-assisted microdissection with corresponding FISH data. The tumor specimen on the top was taken from a pre-menopausal woman with stage IIb IDCA, without amplification of the HER2 gene. The tumor specimen on the bottom was taken from a pre-menopausal woman stage IIIB IDCA and HER2 amplification of 3.3. Green signals = CEP17 probe, orange = HER2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Images of tumors before and after laser-assisted microdissection with corresponding FISH data. The tumor specimen on the top was taken from a pre-menopausal woman with stage IIb IDCA, without amplification of the HER2 gene. The tumor specimen on the bottom was taken from a pre-menopausal woman stage IIIB IDCA and HER2 amplification of 3.3. Green signals = CEP17 probe, orange = HER2.
Mentions: DNA was obtained from pure populations of primary breast tumor cells following laser-assisted microdissection on an AS LMD laser microdissection system (Leica Microsystems, Wetzlar, Germany) [19] (Figure 1). All microdissected sections were examined by the CBCP pathologist, who identified and marked regions of tumor before dissection. To avoid PCR artifacts, ≥ 5,000 cells were captured from each of six consecutive breast tumor sections, with the sixth section reserved for all confirmatory reruns. Referent DNA samples for the archival samples were extracted from disease-free skin or negative lymph node tissue from each patient using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA). Referent DNA for the CBCP samples was obtained from blood clots using Clotspin and Puregene DNA purification kits (Gentra, Minneapolis, MN).

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