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A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels

Oncogene volume 39, pages 5430–5440 (2020)Cite this article

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Abstract

Pan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell-cycle activity in 9515 pan-cancer patients with 32 different tumour types. Boxplots showed that cell-cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all cell cycle score (CCS) tertiles but with increasing frequency as cell-cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent in CCS High tumours (P < 0.001). In Kaplan–Meier analysis, patients whose tumours were CCS Low had a longer Progression Free Interval (PFI) relative to Intermediate or High (P < 0.001) and this significance remained in multivariable analysis (CCS Intermediate: HR = 1.37; 95% CI 1.17–1.60, CCS High: 1.54; 1.29–1.84, CCS Low = Ref). These results demonstrate that whilst similar DNA alterations can be found at all cell-cycle activity levels, some notable exceptions exist. Moreover, independent prognostic information can be derived on a pan-cancer level from a simple measure of cell-cycle activity.

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Fig. 1: CCS score across cancer types and COCA subtypes.
Fig. 2: Top 15 most commonly mutated genes or chromosomal arm-level alterations within CCS subgroups.
Fig. 3: Boxplots comparing frequency of DNA alterations across CCS subgroups.

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Data availability

The data used in this study are publicly available on the NIH website (https://gdc.cancer.gov/about-data/publications/pancanatlas).

Code availablity

R-code to reproduce the main and Supplementary results of this study are publicly available at https://github.com/arianlundberg/PANCAN.analysis.

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Funding

This work was supported by the Iris, Stig och Gerry Castenbäcks Stiftelse for cancer research (to NPT), the King Gustaf V Jubilee Foundation (NPT and JB), BRECT, the Swedish Cancer Society, the Cancer Society in Stockholm Personalised Cancer Medicine (PCM), the King Gustaf V Jubilee Foundation, the Swedish Breast Cancer Association (BRO) and the Swedish Research Council (J. Bergh). CMP was supported by funds from the NCI Breast SPORE program (P50-CA58223-09A1), by R01-CA195754-01, by the Susan G. Komen (SAC-160074) and the Breast Cancer Research Foundation.

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Authors and Affiliations

  1. Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden

    Arian Lundberg, Elinor Löverli, Jonas Bergh & Nicholas P. Tobin

  2. Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA, USA

    Arian Lundberg

  3. Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden

    Linda S. Lindström

  4. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Joel S. Parker & Charles M. Perou

  5. Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Charles M. Perou

  6. Department of Public Health, Oxford University, Oxford, UK

    Jonas Bergh

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  1. Arian Lundberg
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Correspondence to Nicholas P. Tobin.

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Conflict of interest

JB has no conflict of interest related to the present work. Unrelated to the present work, he received research funding from Merck paid to Karolinska Institutet and from Amgen, Bayer, Pfizer, Roche and Sanofi-Aventis paid to Karolinska University Hospital. No personal payments. Payment from UpToDate for a chapter in breast cancer prediction paid to Asklepios Medicine AB. CMP is an equity stockholder, and consultant, for of BioClassifier LLC. CMP and JP are also listed as inventors on patents on the Breast PAM50 Subtyping assay. All remaining authors have declared no conflicts of interest.

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Lundberg, A., Lindström, L.S., Parker, J.S. et al. A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels. Oncogene 39, 5430–5440 (2020). https://doi.org/10.1038/s41388-020-1367-4

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