Abstract
Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
| Original language | English |
|---|---|
| Pages (from-to) | 1853-1864 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 54 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2022 |
| Externally published | Yes |
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The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer. / Garsed, Dale W.; Pandey, Ahwan; Fereday, Sian et al.
In: Nature Genetics, Vol. 54, No. 12, 12.2022, p. 1853-1864.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer
AU - Garsed, Dale W.
AU - Pandey, Ahwan
AU - Fereday, Sian
AU - Kennedy, Catherine J.
AU - Takahashi, Kazuaki
AU - Alsop, Kathryn
AU - Hamilton, Phineas T.
AU - Hendley, Joy
AU - Chiew, Yoke Eng
AU - Traficante, Nadia
AU - Provan, Pamela
AU - Ariyaratne, Dinuka
AU - Au-Yeung, George
AU - Bateman, Nicholas W.
AU - Bowes, Leanne
AU - Brand, Alison
AU - Christie, Elizabeth L.
AU - Cunningham, Julie M.
AU - Friedlander, Michael
AU - Grout, Bronwyn
AU - Harnett, Paul
AU - Hung, Jillian
AU - McCauley, Bryan
AU - McNally, Orla
AU - Piskorz, Anna M.
AU - Saner, Flurina A.M.
AU - Vierkant, Robert A.
AU - Wang, Chen
AU - Winham, Stacey J.
AU - Pharoah, Paul D.P.
AU - Brenton, James D.
AU - Conrads, Thomas P.
AU - Maxwell, George L.
AU - Ramus, Susan J.
AU - Pearce, Celeste Leigh
AU - Pike, Malcolm C.
AU - Nelson, Brad H.
AU - Goode, Ellen L.
AU - DeFazio, Anna
AU - Bowtell, David D.L.
N1 - Funding Information: We thank P. Webb, K. Byth, R. Lupat, J. Ellul and the Peter MacCallum Cancer Centre Research Computing Facility for their contributions to the study. This work was supported by the U.S. Army Medical Research and Materiel Command Ovarian Cancer Research Program (Award No. W81XWH-16-2-0010 and W81XWH-21-1-0401), the National Health and Medical Research Council of Australia (1092856, 1117044 and 2008781 to D.D.L.B., and 1186505 to D.W.G.), and the U.S. National Cancer Institute (P30CA046592 for C.L.P. and P30CA008748 for M.C.P.). This research was made possible by generous support from the Border Ovarian Cancer Awareness Group, the Garvan Research Foundation, the Graf Family Foundation, Mrs Margaret Rose AM, Arthur Coombs and family, and the Piers K Fowler Fund. The Australian Ovarian Cancer Study (AOCS) gratefully acknowledges the cooperation of participating institutions in Australia and the contribution of study nurses, research assistants and all clinical and scientific collaborators. The complete AOCS Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in the study. AOCS was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania, The Cancer Foundation of Western Australia and the National Health and Medical Research Council of Australia (NHMRC; ID199600, ID400413, ID400281). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Cancer Foundation. We thank all the women who participated in the GynBiobank and gratefully acknowledge the Departments of Gynaecological Oncology, Medical Oncology and Anatomical Pathology at Westmead Hospital, Sydney. The Gynaecological Oncology Biobank at Westmead was funded by the NHMRC (ID310670, ID628903), the Cancer Institute NSW (12/RIG/1-17, 15/RIG/1-16) and the Department of Gynaecological Oncology, Westmead Hospital, and acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW (15/TRC/1-01). E.L.C. was supported by NHMRC grant APP1161198. F.A.M.S. was supported by a Swiss National Foundation EarlyPostdoc Fellowship (P2BEP3-172246), Swiss Cancer Research Foundation grant BIL KFS-3942-08-2016 and a Professor Dr Max Cloëtta and Uniscientia Foundation grant. A.M.P. and J.D.B. were supported by Cancer Research UK (A22905). B.H.N. was supported by the BC Cancer Foundation, Canada’s Networks of Centres of Excellence (BioCanRx), Genome BC and the Canada Foundation for Innovation. D.D.L.B. was supported by the U.S. National Cancer Institute U54 program (U54CA209978). Funding Information: We thank P. Webb, K. Byth, R. Lupat, J. Ellul and the Peter MacCallum Cancer Centre Research Computing Facility for their contributions to the study. This work was supported by the U.S. Army Medical Research and Materiel Command Ovarian Cancer Research Program (Award No. W81XWH-16-2-0010 and W81XWH-21-1-0401), the National Health and Medical Research Council of Australia (1092856, 1117044 and 2008781 to D.D.L.B., and 1186505 to D.W.G.), and the U.S. National Cancer Institute (P30CA046592 for C.L.P. and P30CA008748 for M.C.P.). This research was made possible by generous support from the Border Ovarian Cancer Awareness Group, the Garvan Research Foundation, the Graf Family Foundation, Mrs Margaret Rose AM, Arthur Coombs and family, and the Piers K Fowler Fund. The Australian Ovarian Cancer Study (AOCS) gratefully acknowledges the cooperation of participating institutions in Australia and the contribution of study nurses, research assistants and all clinical and scientific collaborators. The complete AOCS Group can be found at www.aocstudy.org . We would like to thank all of the women who participated in the study. AOCS was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania, The Cancer Foundation of Western Australia and the National Health and Medical Research Council of Australia (NHMRC; ID199600, ID400413, ID400281). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Cancer Foundation. We thank all the women who participated in the GynBiobank and gratefully acknowledge the Departments of Gynaecological Oncology, Medical Oncology and Anatomical Pathology at Westmead Hospital, Sydney. The Gynaecological Oncology Biobank at Westmead was funded by the NHMRC (ID310670, ID628903), the Cancer Institute NSW (12/RIG/1-17, 15/RIG/1-16) and the Department of Gynaecological Oncology, Westmead Hospital, and acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW (15/TRC/1-01). E.L.C. was supported by NHMRC grant APP1161198. F.A.M.S. was supported by a Swiss National Foundation EarlyPostdoc Fellowship (P2BEP3-172246), Swiss Cancer Research Foundation grant BIL KFS-3942-08-2016 and a Professor Dr Max Cloëtta and Uniscientia Foundation grant. A.M.P. and J.D.B. were supported by Cancer Research UK (A22905). B.H.N. was supported by the BC Cancer Foundation, Canada’s Networks of Centres of Excellence (BioCanRx), Genome BC and the Canada Foundation for Innovation. D.D.L.B. was supported by the U.S. National Cancer Institute U54 program (U54CA209978). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/12
Y1 - 2022/12
N2 - Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
AB - Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
UR - http://www.scopus.com/inward/record.url?scp=85141490262&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01230-9
DO - 10.1038/s41588-022-01230-9
M3 - Article
C2 - 36456881
AN - SCOPUS:85141490262
SN - 1061-4036
VL - 54
SP - 1853
EP - 1864
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -