A global genome damage score predictive of lung cancer patients outcome

Abstract

Genome damage is a hallmark of human cancer. Efforts at assessing the impact of genome damage on tumor phenotype and patients outcome have focused on measurements of the relative DNA content in tumor cells compared to normal cells and the assessment of allelic loss at single or multiple selected loci that are thought to harbor genes important in cancer biology. We adapted a global, high-resolution genotyping method for determination of global and unbiased allelic loss. We generated a score, termed global genome damage score (GGDS), that is a continuous variable from zero to one and a measure of the extent of damaged DNA in individual tumors. In 71 patients with completely resected non-small-cell lung cancer, the GGDS ranged from 0.0006 to 0.5530 with a median value of 0.0401 indicating that between 0.06 and 55.3% of the genome has allelic loss. Patients with high scores (>0.04) had a significantly worse outcome than those with low scores (median overall survival time 35.5 vs >120.0 months, P=0.006 log-rank test; median disease-free survival 28.3 vs >120.0 months, P=0.003 log-rank test). This suggests that the clinical behavior of lung tumors with low GGDS is relatively benign whereas tumors with high GGDS are aggressive resulting in early death of patients.