Genomic–transcriptomic evolution in lung cancer and metastasis

Martínez-Ruiz, C. et al. (2023) Genomic–transcriptomic evolution in lung cancer and metastasis. Nature, 616, pp. 543-552. (doi: 10.1038/s41586-023-05706-4) (PMID:37046093) (PMCID:PMC10115639)

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Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Dick, Dr Craig and Le Quesne, Professor John and Blyth, Professor Kevin
Authors: Martínez-Ruiz, C., Black, J. R. M., Puttick, C., Hill, M. S., Demeulemeester, J., Larose Cadieux, E., Thol, K., Jones, T. P., Veeriah, S., Naceur-Lombardelli, C., Toncheva, A., Prymas, P., Rowan, A., Ward, S., Cubitt, L., Athanasopoulou, F., Pich, O., Karasaki, T., Moore, D. A., Salgado, R., Colliver, E., Castignani, C., Dietzen, M., Huebner, A., Al Bakir, M., Tanić, M., Watkins, T. B. K., Lim, E. L., Al-Rashed, A. M., Lang, D., Clements, J., Cook, D. E., Rosenthal, R., Wilson, G. A., Frankell, A. M., de Carné Trécesson, S., East, P., Kanu, N., Litchfield, K., Birkbak, N. J., Hackshaw, A., Beck, S., Van Loo, P., Jamal-Hanjani, M., McGranahan, N., Swanton, C., Bakir, M. A., Lim, E. L., Frankell, A. M., Litchfield, K., Birkbak, N. J., Van Loo, P., Lester, J. F., Bajaj, A., Nakas, A., Sodha-Ramdeen, A., Ang, K., Tufail, M., Chowdhry, M. F., Scotland, M., Boyles, R., Rathinam, S., Wilson, C., Marrone, D., Dulloo, S., Fennell, D. A., Matharu, G., Shaw, J. A., Riley, J., Primrose, L., Boleti, E., Cheyne, H., Khalil, M., Richardson, S., Cruickshank, T., Price, G., Kerr, K. M., Benafif, S., Gilbert, K., Naidu, B., Patel, A. J., Osman, A., Lacson, C., Langman, G., Shackleford, H., Djearaman, M., Kadiri, S., Middleton, G., Leek, A., Hodgkinson, J. D., Totten, N., Montero, A., Smith, E., Fontaine, E., Granato, F., Doran, H., Novasio, J., Rammohan, K., Joseph, L., Bishop, P., Shah, R., Moss, S., Joshi, V., Crosbie, P., Gomes, F., Brown, K., Carter, M., Chaturvedi, A., Priest, L., Oliveira, P., Lindsay, C. R., Blackhall, F. H., Krebs, M. G., Summers, Y., Clipson, A., Tugwood, J., Kerr, A., Rothwell, D. G., Kilgour, E., Dive, C., Aerts, H. J. W. L., Schwarz, R. F., Kaufmann, T. L., Szallasi, Z., Kisistok, J., Sokac, M., Diossy, M., Bunkum, A., Stewart, A., Magness, A., Karamani, A., Chain, B., Campbell, B. B., Bailey, C., Abbosh, C., Weeden, C. E., Lee, C., Richard, C., Hiley, C. T., Pearce, D. R., Karagianni, D., Biswas, D., Levi, D., Hoxha, E., Nye, E., Grönroos, E., Gálvez-Cancino, F., Gimeno-Valiente, F., Kassiotis, G., Stavrou, G., Mastrokalos, G., Zhai, H., Lowe, H. L., Matos, I. G., Goldman, J., Reading, J. L., Herrero, J., Rane, J. K., Nicod, J., Lam, J. M., Hartley, J. A., Peggs, K. S., Enfield, K. S. S., Selvaraju, K., Ng, K. W., Chen, K., Dijkstra, K., Grigoriadis, K., Thakkar, K., Ensell, L., Shah, M., Duran, M. V., Litovchenko, M., Sunderland, M. W., Leung, M., Escudero, M., Angelova, M., Sivakumar, M., Chervova, O., Lucas, O., Al-Sawaf, O., Hobson, P., Pawlik, P., Stone, R. K., Bentham, R., Hynds, R. E., Vendramin, R., Saghafinia, S., López, S., Gamble, S., Ung, S. K. A., Quezada, S. A., Vanloo, S., Zaccaria, S., Hessey, S., Boeing, S., Bola, S. K., Denner, T., Marafioti, T., Mourikis, T. P., Spanswick, V., Barbè, V., Lu, W.-T., Hill, W., Liu, W. K., Wu, Y., Naito, Y., Ramsden, Z., Veiga, C., Royle, G., Collins-Fekete, C.-A., Fraioli, F., Ashford, P., Clark, T., Forster, M. D., Lee, S. M., Borg, E., Falzon, M., Papadatos-Pastos, D., Wilson, J., Ahmad, T., Procter, A. J., Ahmed, A., Taylor, M. N., Nair, A., Lawrence, D., Patrini, D., Navani, N., Thakrar, R. M., Janes, S. M., Hoogenboom, E. M., Monk, F., Holding, J. W., Choudhary, J., Bhakhri, K., Scarci, M., Hayward, M., Panagiotopoulos, N., Gorman, P., Khiroya, R., Stephens, R. C. M., Wong, Y. N. S., Bandula, S., Sharp, A., Smith, S., Gower, N., Dhanda, H. K., Chan, K., Pilotti, C., Leslie, R., Grapa, A., Zhang, H., AbdulJabbar, K., Pan, X., Yuan, Y., Chuter, D., MacKenzie, M., Chee, S., Alzetani, A., Cave, J., Scarlett, L., Richards, J., Ingram, P., Austin, S., Lim, E., De Sousa, P., Jordan, S., Rice, A., Raubenheimer, H., Bhayani, H., Ambrose, L., Devaraj, A., Chavan, H., Begum, S., Buderi, S. I., Kaniu, D., Malima, M., Booth, S., Nicholson, A. G., Fernandes, N., Shah, P., Proli, C., Hewish, M., Danson, S., Shackcloth, M. J., Robinson, L., Russell, P., Blyth, K. G., Dick, C., Le Quesne, J., Kirk, A., Asif, M., Bilancia, R., Kostoulas, N., Thomas, M., Swanton, C., and McGranahan, N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature
Publisher:Nature Research
ISSN (Online):1476-4687
Published Online:12 April 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature 616:543–552
Publisher Policy:Reproduced under a Creative Commons License

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