Background

There is compelling molecular and cytogenetic evidence to suggest that abnormalities of chromosome 17, including p53 mutation and HER2 gene amplification, are associated with increased genomic instability, notably higher chromosomal instability (CIN) and poor patient outcome in breast cancer. We examined cytogenetic abnormalities associated with p53 mutation status and the prognostic significance of these associations in primary breast cancer patients.

Method

Formalin fixed paraffin embedded (FFPE) tissue sections from 201 primary breast cancers were analysed using multi-parametric flow cytometry (1). Tumours were sub-grouped into ploidy categories based on their DNA content, thus enabling a robust comparison with clinical and molecular markers of prognosis including p53 mutation status. Array comparative genomic hybridisation (aCGH) on a subset (n=81) of flow sorted tumours enabled a further assessment of genetic instability in the context of overall large scale copy number change.

Results

P53 mutation was independently associated with gain of chromosome 8q24.21 (P=0.04), which houses the c-Myc oncogene. This region also associated with high DNA content tumours (P=0.04), which in turn independently associate with p53 mutant status (P=0.009). Further associations with the gain of 8q24.21 region were observed with the loss of 9q34.2-q34.3 (P<0.001), which independently associates with oestrogen receptor (ER) negative status (P=0.002).

Conclusion

Significant statistical associations were demonstrated between gain of 8q24.21 and loss of 9q34.2-q34.3 regions with p53 mutant, ER negative and high DNA content tumours indicating a significant poor prognostic association of these regions in primary breast cancer. Further, an independent association between 8q24.21 gain and 9q34.2-q34.3 loss suggests an underlying molecular pathway involving these genetic lesions and aggressive breast cancer.