Pan-cancer analysis of the extent and consequences of intra-tumor heterogeneity

By N. Andor, Trevor A. Graham, M. Jansen, L. Xia, C. A. Aktipis, C. Petritsch, Hanlee P. Ji, Carlo C. Maley. Nature Medicine, 2015

702 citations recorded by the source corpus.

Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24–0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71–2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20–1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08–0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/b7a3445ac9c7478a90558315c4b13e0e81f38112

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In Cancer Research

1. A. Marusyk
2. K. Polyak
3. M. Janiszewska
4. R. Weinberg

In Oncology

1. A. Marusyk
2. K. Polyak
3. R. Weinberg
4. Zena Werb
5. D. Hanahan

Citations in the corpus

• Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Both experimental studies and analysis of clinical data support the existence of a “sweet spot” of CIN-related diversity, where intermediate levels, which, balance evolvability with ability to maintain fitness of tumor cell populations, are most dangerous (Andor et al., 2016; Godek et al., 2016).”
• Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, unknown): “…observation that tumors with an extreme level of chromosomal instability appear associated with improved prognosis compared to intermediate levels (Andor et al., 2016; Birkbak et al., 2011), further supports the hypothesis there may be a delicate balance between too much and too little…”