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

被引：24

作者：

Martins, Filipe Correia ^{[1
,2
,3
,4
,5
]}

Couturier, Dominique-Laurent ^{[3
,6
]}

de Santiago, Ines ^{[3
]}

Sauer, Carolin Margarethe ^{[3
]}

Vias, Maria ^{[3
]}

Angelova, Mihaela ^{[4
]}

Sanders, Deborah ^{[3
]}

Piskorz, Anna ^{[3
]}

Hall, James ^{[3
]}

Hosking, Karen ^{[7
]}

Amirthanayagam, Anumithra ^{[5
]}

Cosulich, Sabina ^{[8
]}

Carnevalli, Larissa ^{[8
]}

Davies, Barry ^{[8
]}

Watkins, Thomas B. K. ^{[4
]}

Funingana, Ionut G. ^{[3
,9
]}

Bolton, Helen ^{[5
]}

Haldar, Krishnayan ^{[5
]}

Latimer, John ^{[5
]}

Baldwin, Peter ^{[5
]}

Crawford, Robin ^{[5
]}

Eldridge, Matthew ^{[3
]}

Basu, Bristi ^{[7
,9
]}

Jimenez-Linan, Mercedes ^{[10
]}

Mcpherson, Andrew W. ^{[11
]}

McGranahan, Nicholas ^{[12
]}

Litchfield, Kevin ^{[4
]}

Shah, Sohrab P. ^{[11
]}

McNeish, Iain ^{[13
]}

Caldas, Carlos ^{[3
,9
]}

Evan, Gerard ^{[14
]}

Swanton, Charles ^{[4
,12
]}

Brenton, James D. ^{[3
,9
]}

机构：

[1] Univ Cambridge, Dept Obstet & Gynaecol, Cambridge, England

[2] Univ Cambridge, Expt Med Initiat, Cambridge, England

[3] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[4] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England

[5] Cambridge Univ Hosp, Dept Gynaecol Oncol, Cambridge, England

[6] Univ Cambridge, MRC, Biostat Unit, Cambridge, England

[7] Cambridge Univ Hosp, Cambridge, England

[8] Astrazeneca, Early Oncol R&D, Cambridge, England

[9] Univ Cambridge, Dept Oncol, Cambridge, England

[10] Cambridge Univ Hosp, Dept Histopathol, Cambridge, England

[11] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Computat Oncol, Nyc, NY USA

[12] Univ Coll London Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London, England

[13] Imperial Coll London, Dept Surg & Canc, London, England

[14] Univ Cambridge, Dept Biochem, Cambridge, England

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

欧洲研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

C-MYC; SYNTHETIC LETHALITY; PATHWAYS; PROTEIN; DNA; SIGNATURES; LANDSCAPE; FORMALIN; PLATFORM; REGIONS;

D O I：

10.1038/s41467-022-33870-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine. 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.

引用

页数：14

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