Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer

被引：32

作者：

Burdett, Nikki L. ^{[1
,2
,3
]}

Willis, Madelynne O. ^{[1
]}

Alsop, Kathryn ^{[1
,2
]}

Hunt, Allison L. ^{[4
,5
,6
]}

Pandey, Ahwan ^{[1
]}

Hamilton, Phineas T. ^{[7
]}

Abulez, Tamara ^{[5
,6
,8
]}

Liu, Xuan ^{[9
]}

Hoang, Therese ^{[1
]}

Craig, Stuart ^{[1
]}

Fereday, Sian ^{[1
,2
]}

Hendley, Joy ^{[1
]}

Garsed, Dale W. ^{[1
,2
]}

Milne, Katy ^{[7
]}

Kalaria, Shreena ^{[7
]}

Marshall, Ashley ^{[7
]}

Hood, Brian L. ^{[5
,6
,8
]}

Wilson, Katlin N. ^{[5
,6
,8
]}

Conrads, Kelly A. ^{[5
,6
,8
]}

Pishas, Kathleen, I ^{[1
,2
]}

Ananda, Sumitra ^{[1
,10
,11
,12
]}

Scott, Clare L. ^{[1
,13
]}

Antill, Yoland ^{[14
,15
,16
]}

McNally, Orla ^{[17
,18
]}

Mileshkin, Linda ^{[1
,2
]}

Hamilton, Anne ^{[1
,2
,17
]}

Au-Yeung, George ^{[1
,2
]}

Devereux, Lisa ^{[1
,2
]}

Thorne, Heather ^{[1
,2
]}

Bild, Andrea ^{[19
]}

Bateman, Nicholas W. ^{[6
,8
,20
]}

Maxwell, G. Larry ^{[4
,5
,6
,20
]}

Chang, Jeffrey T. ^{[9
]}

Conrads, Thomas P. P. ^{[5
,6
,8
,20
]}

Nelson, Brad H. ^{[7
,21
,22
]}

Bowtell, David D. L. ^{[1
,2
]}

Christie, Elizabeth L. L. ^{[1
,2
]}

机构：

[1] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia

[3] Eastern Hlth, Dept Med Oncol, Box Hill, Vic, Australia

[4] Womens Hlth Integrated Res Ctr, Inova Hlth Syst, Inova Womens Serv Line, Annandale, Vic, Australia

[5] Uniformed Serv Univ Hlth Sci, Gynecol Canc Ctr Excellence, Dept Obstet & Gynecol, Bethesda, MD USA

[6] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA

[7] Deeley Res Ctr, BC Canc, Victoria, BC, Canada

[8] Henry M Jackson Fdn Advancement Mil Med Inc, Bethesda, MD USA

[9] Univ Texas Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, Houston, TX USA

[10] Western Hlth, Dept Med Oncol, St Albans, Vic, Australia

[11] Univ Melbourne, Dept Med, Western Hlth, St Albans, Vic, Australia

[12] Epworth Healthcare, East Melbourne, Vic, Australia

[13] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia

[14] Monash Univ, Fac Med Nursing & Hlth Sci, Clayton, Vic, Australia

[15] Cabrini Hlth, Malvern, Vic, Australia

[16] Peninsula Hlth, Dept Med Oncol, Frankston, Vic, Australia

[17] Royal Womens Hosp, Parkville, Vic, Australia

[18] Univ Melbourne, Dept Obstet & Gynaecol, Melbourne, Vic, Australia

[19] City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut, Monrovia, CA USA

[20] Uniformed Serv Univ Hlth Sci, John P Murtha Canc Ctr Res Program, Dept Surg, Bethesda, MD USA

[21] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[22] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada

来源：

NATURE GENETICS | 2023年 / 55卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会; 加拿大创新基金会; 英国医学研究理事会;

关键词：

CIRCULATING TUMOR DNA; GERMLINE MUTATIONS; EVOLUTIONARY HISTORY; SOMATIC MUTATIONS; PARP INHIBITOR; GENES; RESISTANCE; SIGNATURES; REVERSION; DETERMINANTS;

D O I：

10.1038/s41588-023-01320-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients. Multiple samples collected at autopsy from women with homologous recombination-deficient high-grade serous ovarian cancer highlight substantial inter- and intratumoral heterogeneity. A plethora of resistance mechanisms were identified within and between patients.

引用

页码：437 / +

页数：33

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