High Levels of Chromosomal Copy Number Alterations and TP53 Mutations Correlate with Poor Outcome in Younger Breast Cancer Patients

Abstract

Prognosis in young patients with breast cancer is generally poor, yet considerable differences in clinical outcomes between individual patients exist. To understand the genetic basis of the disparate clinical courses, tumors were collected from 34 younger women, 17 with good and 17 with poor outcomes, as determined by disease-specific survival during a follow-up period of 17 years. The clinicopathologic parameters of the tumors were complemented with DNA image cytometry profiles, enumeration of copy numbers of eight breast cancer genes by multicolor fluorescence in situ hybridization, and targeted sequence analysis of 563 cancer genes. Both groups included diploid and aneuploid tumors. The degree of intratumor heterogeneity was significantly higher in aneuploid versus diploid cases, and so were gains of the oncogenes MYC and ZNF217. Significantly more copy number alterations were observed in the group with poor outcome. Almost all tumors in the group with long survival were classified as luminal A, whereas triple-negative tumors predominantly occurred in the short survival group. Mutations in PIK3CA were more common in the group with good outcome, whereas TP53 mutations were more frequent in patients with poor outcomes. This study shows that TP53 mutations and the extent of genomic imbalances are associated with poor outcome in younger breast cancer patients and thus emphasize the central role of genomic instability vis-a-vis tumor aggressiveness.