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

Nikki L. Burdett; Madelynne O. Willis; Kathryn Alsop; Allison L. Hunt; Ahwan Pandey; Phineas T. Hamilton; Tamara Abulez; Xuan Liu; Therese Hoang; Stuart Craig; Sian Fereday; Joy Hendley; Dale W. Garsed; Katy Milne; Shreena Kalaria; Ashley Marshall; Brian L. Hood; Katlin N. Wilson; Kelly A. Conrads; Kathleen I. Pishas; Sumitra Ananda; Clare L. Scott; Yoland Antill; Orla McNally; Linda Mileshkin; Anne Hamilton; George Au-Yeung; Lisa Devereux; Heather Thorne; Andrea Bild; Nicholas W. Bateman; G. Larry Maxwell; Jeffrey T. Chang; Thomas P. Conrads; Brad H. Nelson; David D.L. Bowtell; Elizabeth L. Christie

doi:10.1038/s41588-023-01320-2

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

Nikki L. Burdett, Madelynne O. Willis, Kathryn Alsop, Allison L. Hunt, Ahwan Pandey, Phineas T. Hamilton, Tamara Abulez, Xuan Liu, Therese Hoang, Stuart Craig, Sian Fereday, Joy Hendley, Dale W. Garsed, Katy Milne, Shreena Kalaria, Ashley Marshall, Brian L. Hood, Katlin N. Wilson, Kelly A. Conrads, Kathleen I. PishasSumitra Ananda, Clare L. Scott, Yoland Antill, Orla McNally, Linda Mileshkin, Anne Hamilton, George Au-Yeung, Lisa Devereux, Heather Thorne, Andrea Bild, Nicholas W. Bateman, G. Larry Maxwell, Jeffrey T. Chang, Thomas P. Conrads, Brad H. Nelson, David D.L. Bowtell, Elizabeth L. Christie^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	437-450
Number of pages	14
Journal	Nature Genetics
Volume	55
Issue number	3
DOIs	https://doi.org/10.1038/s41588-023-01320-2
State	Published - Mar 2023
Externally published	Yes

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Burdett, N. L., Willis, M. O., Alsop, K., Hunt, A. L., Pandey, A., Hamilton, P. T., Abulez, T., Liu, X., Hoang, T., Craig, S., Fereday, S., Hendley, J., Garsed, D. W., Milne, K., Kalaria, S., Marshall, A., Hood, B. L., Wilson, K. N., Conrads, K. A., ... Christie, E. L. (2023). Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer. Nature Genetics, 55(3), 437-450. https://doi.org/10.1038/s41588-023-01320-2

@article{c0153bb59b8f4ee8b8e51f598e188df0,

title = "Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer",

abstract = "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.",

author = "Burdett, {Nikki L.} and Willis, {Madelynne O.} and Kathryn Alsop and Hunt, {Allison L.} and Ahwan Pandey and Hamilton, {Phineas T.} and Tamara Abulez and Xuan Liu and Therese Hoang and Stuart Craig and Sian Fereday and Joy Hendley and Garsed, {Dale W.} and Katy Milne and Shreena Kalaria and Ashley Marshall and Hood, {Brian L.} and Wilson, {Katlin N.} and Conrads, {Kelly A.} and Pishas, {Kathleen I.} and Sumitra Ananda and Scott, {Clare L.} and Yoland Antill and Orla McNally and Linda Mileshkin and Anne Hamilton and George Au-Yeung and Lisa Devereux and Heather Thorne and Andrea Bild and Bateman, {Nicholas W.} and Maxwell, {G. Larry} and Chang, {Jeffrey T.} and Conrads, {Thomas P.} and Nelson, {Brad H.} and Bowtell, {David D.L.} and Christie, {Elizabeth L.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = mar,

doi = "10.1038/s41588-023-01320-2",

language = "English",

volume = "55",

pages = "437--450",

journal = "Nature Genetics",

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Burdett, NL, Willis, MO, Alsop, K, Hunt, AL, Pandey, A, Hamilton, PT, Abulez, T, Liu, X, Hoang, T, Craig, S, Fereday, S, Hendley, J, Garsed, DW, Milne, K, Kalaria, S, Marshall, A, Hood, BL, Wilson, KN, Conrads, KA, Pishas, KI, Ananda, S, Scott, CL, Antill, Y, McNally, O, Mileshkin, L, Hamilton, A, Au-Yeung, G, Devereux, L, Thorne, H, Bild, A, Bateman, NW, Maxwell, GL, Chang, JT, Conrads, TP, Nelson, BH, Bowtell, DDL & Christie, EL 2023, 'Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer', Nature Genetics, vol. 55, no. 3, pp. 437-450. https://doi.org/10.1038/s41588-023-01320-2

TY - JOUR

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AU - Burdett, Nikki L.

AU - Willis, Madelynne O.

AU - Alsop, Kathryn

AU - Hunt, Allison L.

AU - Pandey, Ahwan

AU - Hamilton, Phineas T.

AU - Abulez, Tamara

AU - Liu, Xuan

AU - Hoang, Therese

AU - Craig, Stuart

AU - Fereday, Sian

AU - Hendley, Joy

AU - Garsed, Dale W.

AU - Milne, Katy

AU - Kalaria, Shreena

AU - Marshall, Ashley

AU - Hood, Brian L.

AU - Wilson, Katlin N.

AU - Conrads, Kelly A.

AU - Pishas, Kathleen I.

AU - Ananda, Sumitra

AU - Scott, Clare L.

AU - Antill, Yoland

AU - McNally, Orla

AU - Mileshkin, Linda

AU - Hamilton, Anne

AU - Au-Yeung, George

AU - Devereux, Lisa

AU - Thorne, Heather

AU - Bild, Andrea

AU - Bateman, Nicholas W.

AU - Maxwell, G. Larry

AU - Chang, Jeffrey T.

AU - Conrads, Thomas P.

AU - Nelson, Brad H.

AU - Bowtell, David D.L.

AU - Christie, Elizabeth L.

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

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U2 - 10.1038/s41588-023-01320-2

DO - 10.1038/s41588-023-01320-2

M3 - Article

C2 - 36849657

AN - SCOPUS:85149136639

SN - 1061-4036

VL - 55

SP - 437

EP - 450

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

Abstract

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