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

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 identified five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reasoned that their strong selection should prioritise them as key biomarkers for targeted therapies. We used primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number was 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 was 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 was independently observed in squamous lung cancer and triple negative breast cancer. These results suggest that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001008716	This dataset consists of shallow whole genome sequencing data and amplicon sequencing data for 26 ovarian cancer patients (21 high-grade serous ovarian cancer, 4 low-grade serous ovarian cancer and 1 clear cell ovarian cancer). The data are provided as single end FASTQ files for the shallow whole genome sequencing data (31 libraries) and paired end FASTQ files for the amplicon sequencing data (98 libraries).	Illumina HiSeq 2500 Illumina HiSeq 4000	26

Publications	Citations
Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer. Martins FC, Couturier DL, de Santiago I, Sauer CM, Vias M, Angelova M, Sanders D, Piskorz A, Hall J, Hosking K, Amirthanayagam A, Cosulich S, Carnevalli L, Davies B, Watkins TBK, Funingana IG, Bolton H, Haldar K, Latimer J, Baldwin P, Crawford R, Eldridge M, Basu B, Jimenez-Linan M, Mcpherson AW, McGranahan N, Litchfield K, Shah SP, McNeish I, Caldas C, Evan G, Swanton C, Brenton JD. Nat Commun 13: 2022 6360	9

Publications

Citations

Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
Martins FC, Couturier DL, de Santiago I, Sauer CM, Vias M, Angelova M, Sanders D, Piskorz A, Hall J, Hosking K, Amirthanayagam A, Cosulich S, Carnevalli L, Davies B, Watkins TBK, Funingana IG, Bolton H, Haldar K, Latimer J, Baldwin P, Crawford R, Eldridge M, Basu B, Jimenez-Linan M, Mcpherson AW, McGranahan N, Litchfield K, Shah SP, McNeish I, Caldas C, Evan G, Swanton C, Brenton JD. Nat Commun 13: 2022 6360