Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients

Johanna Oltmann, Kerstin Heselmeyer-Haddad, Leanora S. Hernandez, Rüdiger Meyer, Irianna Torres, Yue Hu, Natalie Doberstein, J. Keith Killian, David Petersen, Yuelin Jack Zhu, Daniel C. Edelman, Paul S. Meltzer, Russell Schwartz, E. Michael Gertz, Alejandro A. Schäffer, Gert Auer, Jens K. Habermann, Thomas Ried*

*Corresponding author for this work
6 Citations (Scopus)


The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy, determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective. We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients.

Original languageEnglish
JournalGenes Chromosomes and Cancer
Issue number4
Pages (from-to)165-175
Number of pages11
Publication statusPublished - 01.04.2018

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)


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