Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity

Benetkiewicz, Magdalena; Piotrowski, Arkadiusz; Ståhl, Teresita Díaz de; Jankowski, Michał; Bała, Dariusz; Hoffman, Jacek; Śrutek, Ewa; Laskowski, Ryszard; Zegarski, Wojciech; Dumanski, Jan P.

doi:10.3892/ijo.29.4.935

Cited by 20 publications

(25 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this finding likely reflects the heterogeneity of different clones of cells having different genetic profiles that are present within a primary tumor, which is related to the multistage process of cancer development. Our results and others from primary breast tumors suggest frequent intratumoral heterogeneity of genetic aberrations 12,15,[35][36][37][38] implying a coexistence, within the same mass of primary tumor, of different cell subpopulations with different genetic profiles. Metastasis is likely established by a minority of cells from the primary tumor, which migrate to a single distant site.…”

Section: Discussionmentioning

confidence: 89%

“…All hybridizations of cancer-derived DNA were carried out against blood DNA from a healthy female control, which was previously used in multiple studies. 15,16,18 Results from two hybridizations for each primary tumor and from two hybridizations for each metastasis were merged and initially analyzed as separate experiments. For scoring and visualization of copy number changes, we applied the rank segmentation procedure using Nexus-CGH software.…”

Section: K Genomic Profiling Of Primary Tumors and Matched Aln Metamentioning

confidence: 99%

“…For each patient, we carried out four hybridizations (duplicates of primary tumor and metastasis) to 32K BAC arrays, according to a well-established scheme of dyeswap experiments as described earlier. [15][16][17][18] Image acquisition was performed using the GenePix 4000B scanner (Axon Instruments Inc, Union City, CA, USA). Analysis of hybridization intensity was carried out using the GenePixPro v6 image analysis software (Axon Instruments).…”

Section: Patient Materialsmentioning

confidence: 99%

“…The motivation for this study stems from our previous analysis of genetic variation and genetic heterogeneity in somatic cells, both for normal and tumor-derived samples. [15][16][17] One of our previous reports, surveying B1% of the human genome, suggested a frequent intratumoral (within the same primary tumor) heterogeneity of genetic aberrations in breast cancer. 15 We therefore hypothesized that there likely exist differences between the genetic profiles of primary tumors and corresponding metastases from the same patient.…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17] One of our previous reports, surveying B1% of the human genome, suggested a frequent intratumoral (within the same primary tumor) heterogeneity of genetic aberrations in breast cancer. 15 We therefore hypothesized that there likely exist differences between the genetic profiles of primary tumors and corresponding metastases from the same patient. Global genome copy number variation (CNV) analysis of 13 breast cancer patients revealed frequent genetic differences between matched primary breast tumors and ALN metastasis and these revealed previously characterized biomarkers of disease progression.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

et al. 2010

Self Cite

View full text Add to dashboard Cite

Breast cancer is a major cause of morbidity and mortality in women and its metastatic spread is the principal reason behind the fatal outcome. Metastasis-related research of breast cancer is however underdeveloped when compared with the abundant literature on primary tumors. We applied an unexplored approach comparing at high resolution the genomic profiles of primary tumors and synchronous axillary lymph node metastases from 13 patients with breast cancer. Overall, primary tumors displayed 20% higher number of aberrations than metastases. In all but two patients, we detected in total 157 statistically significant differences between primary lesions and matched metastases. We further observed differences that can be linked to metastatic disease and there was also an overlapping pattern of changes between different patients. Many of the differences described here have been previously linked to poor patient survival, suggesting that this is a viable approach toward finding biomarkers for disease progression and definition of new targets useful for development of anticancer drugs. Frequent genetic differences between primary tumors and metastases in breast cancer also question, at least to some extent, the role of primary tumors as a surrogate subject of study for the systemic disease.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: K Genomic Profiling Of Primary Tumors and Matched Aln Metamentioning

confidence: 99%

Section: Patient Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

Two distinct amplification events of the c‐myc locus in a colorectal tumour

Farina

Bellavia

Tagliavia

et al. 2008

Journal Cellular Physiology

View full text Add to dashboard Cite

Southern hybridisation of genomic DNA extracted from a human primary colorectal carcinoma revealed amplification of a fragment containing the wild-type c-myc locus. Two additional rearranged DNA fragments, lying upstream of c-myc, fused to distant non-contiguous sequences from the same chromosome, with an opposite configuration (head to head vs. head to tail), were also found to be amplified. Sequences analysis suggested that these rearrangements resulted from illegitimate recombination at two distinct points within the DNA sequence just upstream of the c-myc ORF and further that these events triggered two different amplification mechanisms, only one of which, involving a strand invasion event following DNA double strand breaks, increased the copy number of the c-myc ORF.

show abstract

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

Geyer

Weigelt

Natrajan

et al. 2010

The Journal of Pathology

187

159

View full text Add to dashboard Cite

Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2 ) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.

show abstract

Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity

Cited by 20 publications

References 18 publications

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

Two distinct amplification events of the c‐myc locus in a colorectal tumour

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

Contact Info

Product

Resources

About