Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer Journal Article

   

Authors:	Martins, F. C.; Couturier, D. L.; de Santiago, I.; Sauer, C. M.; 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, I. G.; Bolton, H.; Haldar, K.; Latimer, J.; Baldwin, P.; Crawford, R.; Eldridge, M.; Basu, B.; Jimenez-Linan, M.; McPherson, A. W.; McGranahan, N.; Litchfield, K.; Shah, S. P.; McNeish, I.; Caldas, C.; Evan, G.; Swanton, C.; Brenton, J. D.
Article Title:	Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Abstract:	Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine. © 2022, The Author(s).
Keywords:	cancer chemotherapy; controlled study; human tissue; treatment response; methylation; somatic mutation; genetics; doxorubicin; paclitaxel; antineoplastic agent; ovarian neoplasms; chromosome; metabolism; cell survival; carboplatin; enzyme inhibition; gene amplification; gene expression; prevalence; protein; cohort analysis; genetic association; enzyme activation; in vitro study; pathology; drug development; chemosensitivity; phosphatidylinositol 3 kinase; dna methylation; ovary tumor; drug response; ovary carcinoma; chromosomal instability; cystadenocarcinoma, serous; oncogene k ras; tumor gene; protein p21; proto-oncogene proteins p21(ras); mtor signaling; pik3ca gene; oncogene myc; cystadenocarcinoma; personalized medicine; stratification; dna copy number variations; genetic correlation; molecularly targeted therapy; copy number variation; triple negative breast cancer; mammalian target of rapamycin complex 1; phosphatidylinositol 3-kinases; tor serine-threonine kinases; target of rapamycin kinase; mammalian target of rapamycin complex 2; akt signaling; ccne1 gene; tumor spheroid; high grade serous ovarian carcinoma; tert gene; phosphatidylinositol 4,5 bisphosphate 3 kinase; cancer; humans; human; female; article; squamous cell lung carcinoma; class i phosphatidylinositol 3-kinases; mechanistic target of rapamycin complex 1; somaclonal variation
Journal Title:	Nature Communications
Volume:	13
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2022-10-26
Start Page:	6360
Language:	English
DOI:	10.1038/s41467-022-33870-0
PUBMED:	36289203
PROVIDER:	scopus
PMCID:	PMC9606297
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85140579864&doi=10.1038%2fs41467-022-33870-0&partnerID=40&md5=de0c86b9269814ce3e06b2b6b69083e8
Notes:	Article -- Export Date: 1 December 2022 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/200512