Reclassifying tumour cell cycle activity in terms of its tissue of origin

Genomic alterations resulting in loss of control over the cell cycle is a fundamental hallmark of human malignancies. Whilst pan-cancer studies have broadly assessed tumour genomics and their impact on oncogenic pathways, analyses taking the baseline signalling levels in normal tissue into account are lacking. To this end, we aimed to reclassify the cell cycle activity of tumours in terms of their tissue of origin and determine if any common DNA mutations, chromosome arm-level changes or signalling pathways contribute to an increase in baseline corrected cell cycle activity. Combining normal tissue and pan-cancer data from over 13,000 samples we demonstrate that tumours of gynaecological origin show the highest levels of corrected cell cycle activity, partially owing to hormonal signalling and gene expression changes. We also show that normal and tumour tissues can be separated into groups (quadrants) of low/high cell cycle activity and propose the hypothesis of an upper limit on these activity levels in tumours. Published version This work was supported by the Iris, Stig och Gerry Castenbäcks Stiftelse for cancer research (N.P.T.); the King Gustaf V Jubilee Foundation (N.P.T.); the Stockholm Cancer Society (Cancerföreningen i Stockholm to L.S.L.); the Swedish Cancer Society (Cancerfonden, N.P.T. grant number: 200802; L.S.L. grant number: 190140); the Swedish Research Council (Vetenskapsrådet, grant number 2020-02466 to L.S.L); the Swedish Research Council for Health, Working life and Welfare, (FORTE, grant number 2019-00477 to L.S.L.); ALF medicine (grant number LS2018-1157 to L.S.L.) and the Gösta Milton Donation Fund (Stiftelsen Gösta Miltons donationsfond, to L.S.L. Open access funding provided by Karolinska Institute.