Amplification of Stem Genes: New Potential Metastatic Makers in Patients with an Early Form of Breast Cancer

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Abstract

Background

According to our previous studies, the presence of amplifications of stem genes can lead to their ectopic expression and this is associated with an increased activity of tumor stem cells in these patients. This leads to a high aggressiveness of the tumor and the development of metastatic disease. The aim was to evaluate the prognostic significance of the presence of amplifications of stem genes and their expression in patients with early breast cancer (BC).

Methods

The study included 28 patients with T ₁N _xM ₀ BC. We used surgical specimens, including formalin-fixed paraffin-embedded archive materials, for 8 patients. A microarray analysis was performed on high-density DNA chips from CytoScanHDArray to assess the status of copy number aberration (CNA) of stem genes locus. Gene expression was assessed using RT-qPCR.

Results

CNA analysis of the studied tumors of patients without chemotherapy showed that 17/18 patients without metastases did not have two or more amplifications of chromosomal regions. Ten patients had visceral metastases. In 9/10 of these patients in the primary tumor there were two or more amplifications of the stem genes locus. Two or more amplifications of stem genes locus were found in 12 patients with stage I. Hematogenous metastases did not develop in all patients. Comparison of metastasis-free survival rates in groups of patients with 1 or without amplifications and with two or more amplifications showed statistically significant differences ( P = 0.01).

Conclusion

Our studies have shown that the presence of clones with two or more amplifications of stem gene in patients with BC T ₁N _xM ₀ has a significant prognostic value and determines an unfavorable prognosis for distant metastasis.

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Most cited references 20

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Impact of DNA amplification on gene expression patterns in breast cancer.

Maija Wolf, Sampsa Hautaniemi, Guido Sauter … (2002)

Genetic changes underlie tumor progression and may lead to cancer-specific expression of critical genes. Over 1100 publications have described the use of comparative genomic hybridization (CGH) to analyze the pattern of copy number alterations in cancer, but very few of the genes affected are known. Here, we performed high-resolution CGH analysis on cDNA microarrays in breast cancer and directly compared copy number and mRNA expression levels of 13,824 genes to quantitate the impact of genomic changes on gene expression. We identified and mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12 Mb. Throughout the genome, both high- and low-level copy number changes had a substantial impact on gene expression, with 44% of the highly amplified genes showing overexpression and 10.5% of the highly overexpressed genes being amplified. Statistical analysis with random permutation tests identified 270 genes whose expression levels across 14 samples were systematically attributable to gene amplification. These included most previously described amplified genes in breast cancer and many novel targets for genomic alterations, including the HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in 10.2% of primary breast cancers and associated with poor patient prognosis. In conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose overexpression is attributable to gene amplification. These genes may provide insights to the clonal evolution and progression of breast cancer and highlight promising therapeutic targets.

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Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.

Linda J. M. Bryant, J Dignam, N. Wolmark … (2001)

Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate. Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were two-sided. Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.

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Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers.

Susan Brown, SUSAN E HANKINSON (2015)

Data from laboratory and epidemiologic studies support a relationship between endogenous hormones and the increased risk of several female cancers. In epidemiologic studies, consistent associations have been observed between risk of breast, ovarian and endometrial cancers and reproductive and hormonal risk factors such as high postmenopausal body mass index (BMI) and postmenopausal hormone use, which suggest the importance of endogenous hormones in the etiology of these diseases. The relationship between circulating estrogen levels in postmenopausal women and the risk of breast cancer is well established, with an approximately 2-fold higher risk among women in the top 20-25% (versus bottom 20-25%) of levels. However, data evaluating the relationship between endogenous estrogens and premenopausal breast cancer risk are more limited and less consistent. Two studies to date have evaluated the relationship between circulating estrogens and breast cancer risk by menstrual cycle phase at blood collection and only one study has examined this relationship by menopausal status at diagnosis. Three prospective studies have evaluated circulating estrogen levels and endometrial cancer risk in postmenopausal women, with consistent strong positive associations reported (with relative risks of 2-4 comparing high versus low hormone levels), while this relationship has not been studied in premenopausal women. Compared to breast and endometrial cancers, reproductive and hormonal characteristics such as postmenopausal hormone use are generally weaker and less consistent risk factors for ovarian cancer, and the only small prospective study conducted to date indicated a non-significant positive relationship between circulating estrogen levels and ovarian cancer risk. In this review, we summarize current evidence and identify key areas to be addressed in future epidemiologic studies of endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Copyright © 2015 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): J Korean Med Sci

Journal ID (iso-abbrev): J. Korean Med. Sci

Journal ID (publisher-id): JKMS

Title: Journal of Korean Medical Science

Publisher: The Korean Academy of Medical Sciences

ISSN (Print): 1011-8934

ISSN (Electronic): 1598-6357

Publication date (Electronic): 15 November 2019

Publication date Collection: 23 December 2019

Volume: 34

Issue: 49

Electronic Location Identifier: e312

Affiliations

[1 ]Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences Tomsk, Russian Federation.

[2 ]Department of General Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation.

Author notes

Address for Correspondence: Matvey M. Tsyganov, PhD. Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634050 Tomsk, Russian Federation. TsyganovMM@ 123456yandex.ru

Author information

Matvey M. Tsyganov https://orcid.org/0000-0001-7419-4512

Marina K. Ibragimova https://orcid.org/0000-0001-8815-2786

Alina M. Pevzner https://orcid.org/0000-0002-9657-9058

Artem V. Doroshenko https://orcid.org/0000-0001-8846-9636

Elena M. Slonimskaya https://orcid.org/0000-0003-4382-5697

Nikolai V. Litviakov https://orcid.org/0000-0002-0714-8927

Article

DOI: 10.3346/jkms.2019.34.e312

PMC ID: 6926101

PubMed ID: 31858753

SO-VID: f77ac67a-7660-4780-90b1-3dcb05fddea8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 09 August 2019

Date accepted : 16 September 2019

Funding

Funded by: Russian Science Foundation, CrossRef https://doi.org/10.13039/501100006769;

Award ID: 17-15-012-03

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Amplification of Stem Genes: New Potential Metastatic Makers in Patients with an Early Form of Breast Cancer

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Abstract

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Karger: Oncology

Most cited references 20

Impact of DNA amplification on gene expression patterns in breast cancer.

Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.

Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers.

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