Somatic chromosomal number alterations affecting driver genes inform in-vitro and clinical drug response in high-grade serous ovarian cancer

Correia Martins, F.; Couturier, D.-L.; Santiago, I.; Sauer, C.; Vias, M.; Angelova, M.; Sanders, D.; Piskorz, A.; Hall, J.; Hosking, K.; Amirthanayagam, A.; Cosulich, S.; Carnevalli, L.; Davies, B.; Watkins, T. B. K.; Funingana, G.; Bolton, H.; Haldar, K.; Latimer, J.; Baldwin, P.; Crawford, R.; Eldridge, M.; Basu, B.; Jimenez-Linan, M.; McGranahan, N.; Litchfield, K.; Shah, S.; McNeish, I.; Caldas, C.; Evan, G.; Swanton, C.; Brenton, J. D.

doi:10.1101/2020.10.04.325365

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bioRxiv · 10.1101/2020.10.04.325365

Somatic chromosomal number alterations affecting driver genes inform in-vitro and clinical drug response in high-grade serous ovarian cancer

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Abstract

The genomic complexity and heterogeneity of high-grade serous ovarian cancer (HGSOC) has hampered the realisation of successful therapies and effective personalised treatment is an unmet clinical need. Here we show that primary HGSOC spheroid models can be used to predict drug response and use them to demonstrate that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and drug response. These genes are often located in areas of the genome with frequent clonal SCNAs. MYC chromosomal copy number is associated with ex-vivo and clinical response to paclitaxel and ex-vivo response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context to MYC-amplified HGSOC is mostly due to increased prevalence of SCNAs in genes from the PI3K pathway. These results suggest that SCNAs encompassing driver genes could be used to inform therapeutic response in the context of clinical trials testing personalised medicines.

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Correia Martins, F., Couturier, D.-L., Santiago, I., Sauer, C., Vias, M., Angelova, M., Sanders, D., Piskorz, A., Hall, J., Hosking, K., Amirthanayagam, A., Cosulich, S., Carnevalli, L., Davies, B., Watkins, T. B. K., Funingana, G., Bolton, H., Haldar, K., Latimer, J., Baldwin, P., Crawford, R., Eldridge, M., Basu, B., Jimenez-Linan, M., McGranahan, N., Litchfield, K., Shah, S., McNeish, I., Caldas, C., Evan, G., Swanton, C., Brenton, J. D.. 2020-10-04. Somatic chromosomal number alterations affecting driver genes inform in-vitro and clinical drug response in high-grade serous ovarian cancer. https://doi.org/10.1101/2020.10.04.325365

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