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Breast tumors induced by high-dose radiation display similar genetic profiles

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Background

Women who received mantle-field irradiation following Hodgkin's lymphoma (HL) have an age-dependent increased risk of developing breast cancer. It has been estimated that approximately 90% of the breast carcinomas in these patients is a result of their radiation treatment, which makes this series extremely appropriate to determine a potentially radiation-induced genomic profile.

Methods

In this study we have used array-comparative genomic hybridization (array-CGH) and gene expression profiling (GEP) technology to assess the genomic and gene expression changes in radiation-induced breast tumors. For genomic profiling we used DNA isolated from paraffin-embedded primary breast tumors of breast following HL (BfHL) patients (n = 29). These DNAs were hybridized to a small custom-designed BAC array containing 180 clones specifically selected on their function in the DNA-damage repair pathway or breast cancer susceptibility. For gene expression profiling, RNA was isolated from fresh-frozen tissue samples of 13 BfHL patients and hybridized on 35K human oligo-array as well as from sporadic breast tumors that were included as controls, matched for age at diagnosis and no exposure to radiation.

Results

Hierarchical clustering of all the array-CGH data divided the samples into two groups. One cluster consisted of the tumors that had developed in the unprotected area of the breast that received high-dose radiation (20–40 Gy) during treatment. These tumors showed a significantly higher frequency of amplifications and deletions than those that had developed in the low-dose radiation (1–10 Gy) breast area and the control breast tumors. We performed supervised classification on the two groups in order to construct a predictor for identification of tumors that occurred in high-dose irradiation or low-dose irradiation fields. A classifier employing 15 BAC clones achieved the best cross-validation performance, and had an associated validation performance of 91.7%.

Hierarchical clustering of the GEP data was performed using 6111 significantly differently expressed oligomers, which resulted in a clustering of the so-called radiation-induced tumors separate from the sporadic tumors (software program Genesis). A supervised classification strategy of these two groups revealed 50 significant genes that could differentiate low-dose and high-dose radiation BfHL versus sporadic tumors. Importantly, the 'radiation profile' found with the array-CGH could be confirmed by the GEP data; for example, deleted genomic regions showed downregulation of expression.

Conclusion

Our preliminary results indicate that low-dose radiation as well as the high-dose radiation-induced tumors can be distinguished from sporadic tumors on the basis of their genomic and expression profile.

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Broeks, A., de Kemp, S., Bakker, W. et al. Breast tumors induced by high-dose radiation display similar genetic profiles. Breast Cancer Res 7, P4.23 (2005) doi:10.1186/bcr1153

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Keywords

  • Breast Tumor
  • Supervise Classification
  • Genomic Profile
  • Sporadic Tumor
  • Unprotected Area