Abstract
BackgroundIt has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH).MethodsTumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested.ResultsThe mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers.ConclusionsThus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A-bomb radiation may affect the increased amount of CNA as a hallmark of GIN and, subsequently, be associated with a higher histologic grade in breast cancer found in A-bomb survivors.
Highlights
It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors
We evaluated the impact of A-bomb exposure, age at the time of diagnosis, storage time, histological grade according to the modified Bloom-Richardson histologic grading system [23], derivative log ratio spread (DLRSpread), which estimates the log ratio noise by calculating the spread of log ratio differences between consecutive probes along all chromosomes, HER2 amplification and C-MYC amplification determined by fluorescence in situ hybridization (FISH) on genomic instability (GIN) using analysis of covariance which is a technique that combines the features of analysis of variance and regression
As a quality assessment measure, we examined the concordance of the dye-flip analysis and the correlation between array comparative genomic hybridization (aCGH) and FISH results concerning HER2 and C-MYC oncogene amplification
Summary
It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH). Our recent study demonstrated an association of HER2 and C-MYC oncogene amplification in breast cancers among A-bomb survivors with radiation exposure [15]. It is conceivable that radiation from the A-bomb 65 years ago may have induced a higher level of GIN in A-bomb survivors as a long-lasting health effect which is associated with the development of oncogene amplifications and subsequent carcinogenesis. The crucial mechanisms that can account for a radiation effect inducing GIN on the whole genome of breast cancers in Abomb survivors remains elusive
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