Global genome damage is predictive of cancer patients’ outcome

Abstract

9542 Background: Genome damage is a hallmark of human cancer. Efforts at assessing the impact of global genome damage on tumor phenotype and patients’ outcome have focused on measurements of the relative DNA content in tumor cells compared to normal cells (DNA index) and the assessment of allele loss (loss of heterozygosity, LOH) at single or multiple selected loci that are thought to harbor genes important in cancer biology. Methods: We have adapted a global, high-resolution genotyping method for determination of global and unbiased genome damage and generated a global genome damage score (GGDS), which is a measure of the extent of damaged DNA in individual tumors. The score is a continuous variable from zero to one where zero indicates absence of any damage and one indicates complete damage. Results: In surgically resected human non-small-cell lung cancers, the GGDS ranged from 0.003 to 0.204 indicating that between 0.3–20.4% of the genome is damaged. Patients with high scores (>0.049) had a significantly worse outcome and their tumors expressed DNA damage repair genes at lower levels than those with low scores (median overall survival time 38.3 months vs. 94.0 months, p=0.007). The expression of genes involved in DNA damage repair was inversely correlated with GGDS. Conclusions: Our study of global high-resolution genome damage analysis in non-small-cell lung cancer convincingly demonstrates a statistically significant and clinically meaningful association with the in vivo tumor phenotype. This implies that the clinical behavior of tumors with low GGDS is relatively benign while tumors with high GGDS are aggressive resulting in early death of patients. Since GGDS determination is a robust and reliable technology, it can easily be integrated into clinical decisions on cancer care. For instance, adjuvant treatment of epithelial malignancies benefits only a minority of patients while toxicity is substantial. GGDS may prove useful in selecting patients at high risk for tumor-associated mortality for adjuvant therapeutic interventions. No significant financial relationships to disclose.