Concurrent RB1 Loss and <i>BRCA</i> Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma-Reference-Cited by-同舟云学术

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Published:2024-06-05 Issue:16 Volume:30 Page:3481-3498
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
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Author:

Saner Flurina A.M.¹²^ORCID,Takahashi Kazuaki¹³^ORCID,Budden Timothy⁴⁵^ORCID,Pandey Ahwan¹^ORCID,Ariyaratne Dinuka¹^ORCID,Zwimpfer Tibor A.¹^ORCID,Meagher Nicola S.⁴⁶^ORCID,Fereday Sian¹⁷^ORCID,Twomey Laura¹^ORCID,Pishas Kathleen I.¹⁷^ORCID,Hoang Therese¹^ORCID,Bolithon Adelyn⁴⁸^ORCID,Traficante Nadia¹⁷^ORCID, ,Alsop Kathryn¹⁷^ORCID,Christie Elizabeth L.¹⁷^ORCID,Kang Eun-Young⁹^ORCID,Nelson Gregg S.¹⁰^ORCID,Ghatage Prafull¹⁰^ORCID,Lee Cheng-Han¹¹^ORCID,Riggan Marjorie J.¹²^ORCID,Alsop Jennifer¹³^ORCID,Beckmann Matthias W.¹⁴^ORCID,Boros Jessica¹⁵¹⁶¹⁷^ORCID,Brand Alison H.¹⁶¹⁷^ORCID,Brooks-Wilson Angela¹⁸^ORCID,Carney Michael E.¹⁹^ORCID,Coulson Penny²⁰^ORCID,Courtney-Brooks Madeleine²¹^ORCID,Cushing-Haugen Kara L.²²^ORCID,Cybulski Cezary²³^ORCID,El-Bahrawy Mona A.²⁴^ORCID,Elishaev Esther²⁵^ORCID,Erber Ramona²⁶^ORCID,Gayther Simon A.²⁷^ORCID,Gentry-Maharaj Aleksandra²⁸²⁹^ORCID,Gilks C. Blake³⁰^ORCID,Harnett Paul R.¹⁷³¹^ORCID,Harris Holly R.²²³²^ORCID,Hartmann Arndt²⁶^ORCID,Hein Alexander¹⁴^ORCID,Hendley Joy¹^ORCID,Hernandez Brenda Y.³³^ORCID,Jakubowska Anna²³³⁴^ORCID,Jimenez-Linan Mercedes³⁵^ORCID,Jones Michael E.²⁰^ORCID,Kaufmann Scott H.³⁶^ORCID,Kennedy Catherine J.¹⁵¹⁶¹⁷^ORCID,Kluz Tomasz³⁷^ORCID,Koziak Jennifer M.³⁸^ORCID,Kristjansdottir Björg³⁹^ORCID,Le Nhu D.⁴⁰^ORCID,Lener Marcin⁴¹^ORCID,Lester Jenny⁴²^ORCID,Lubiński Jan²³^ORCID,Mateoiu Constantina⁴³^ORCID,Orsulic Sandra⁴²^ORCID,Ruebner Matthias¹⁴^ORCID,Schoemaker Minouk J.²⁰^ORCID,Shah Mitul¹³^ORCID,Sharma Raghwa⁴⁴^ORCID,Sherman Mark E.⁴⁵^ORCID,Shvetsov Yurii B.³⁴^ORCID,Soong T. Rinda²⁵^ORCID,Steed Helen⁴⁶⁴⁷^ORCID,Sukumvanich Paniti²¹^ORCID,Talhouk Aline⁴⁸⁴⁹^ORCID,Taylor Sarah E.²¹^ORCID,Vierkant Robert A.⁵⁰^ORCID,Wang Chen⁵¹^ORCID,Widschwendter Martin⁵²^ORCID,Wilkens Lynne R.³⁴^ORCID,Winham Stacey J.⁵¹^ORCID,Anglesio Michael S.⁴⁸⁴⁹^ORCID,Berchuck Andrew¹²^ORCID,Brenton James D.⁵³^ORCID,Campbell Ian¹⁷^ORCID,Cook Linda S.⁵⁴⁵⁵^ORCID,Doherty Jennifer A.⁵⁶^ORCID,Fasching Peter A.¹⁴^ORCID,Fortner Renée T.⁵⁷⁵⁸^ORCID,Goodman Marc T.⁵⁹^ORCID,Gronwald Jacek²³^ORCID,Huntsman David G.³⁰⁴⁸⁴⁹⁶⁰^ORCID,Karlan Beth Y.⁴²^ORCID,Kelemen Linda E.⁶¹^ORCID,Menon Usha²⁸^ORCID,Modugno Francesmary²¹⁶²⁶³^ORCID,Pharoah Paul D.P.¹³⁶⁴⁶⁵^ORCID,Schildkraut Joellen M.⁶⁶^ORCID,Sundfeldt Karin⁴⁰^ORCID,Swerdlow Anthony J.²⁰⁶⁷^ORCID,Goode Ellen L.⁶⁸^ORCID,DeFazio Anna⁶¹⁵¹⁶¹⁷^ORCID,Köbel Martin⁹^ORCID,Ramus Susan J.⁴⁸^ORCID,Bowtell David D.L.¹⁷^ORCID,Garsed Dale W.¹⁷^ORCID

Affiliation:

1. Peter MacCallum Cancer Centre, Melbourne, Australia. 1

2. Department of Obstetrics and Gynecology, Bern University Hospital and University of Bern, Bern, Switzerland. 2

3. Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan. 3

4. School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, Australia. 4

5. Skin Cancer and Ageing Lab, Cancer Research United Kingdom Manchester Institute, The University of Manchester, Manchester, United Kingdom. 5

6. The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Sydney, Australia. 6

7. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia. 7

8. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, Australia. 8

9. Department of Pathology and Laboratory Medicine, Foothills Medical Center, University of Calgary, Calgary, Canada. 9

10. Division of Gynecologic Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada. 10

11. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada. 11

12. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina. 12

13. Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. 13

14. Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany. 14

15. Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia. 15

16. Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia. 16

17. The University of Sydney, Sydney, Australia. 17

18. Canada’s Michael Smith Genome Sciences Centre, Vancouver, Canada. 18

19. Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii. 19

20. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom. 20

21. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 21

22. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington. 22

23. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland. 23

24. Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, United Kingdom. 24

25. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 25

26. Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany. 26

27. Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California. 27

28. MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom. 28

29. Department of Women’s Cancer, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, United Kingdom. 29

30. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. 30

31. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia. 31

32. Department of Epidemiology, University of Washington, Seattle, Washington. 32

33. University of Hawaii Cancer Center, Honolulu, Hawaii. 33

34. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. 34

35. Department of Histopathology, Addenbrooke’s Hospital, Cambridge, United Kingdom. 35

36. Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota. 36

37. Department of Gynecology and Obstetrics, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland. 37

38. Alberta Health Services-Cancer Care, Calgary, Canada. 38

39. Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden. 39

40. Cancer Control Research, BC Cancer Agency, Vancouver, Canada. 40

41. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland. 41

42. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California. 42

43. Department of Pathology, University of Gothenburg, Gothenburg, Sweden. 43

44. Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, Australia. 44

45. Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida. 45

46. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. 46

47. Section of Gynecologic Oncology Surgery, North Zone, Alberta Health Services, Edmonton, Canada. 47

48. British Columbia’s Gynecological Cancer Research Team (OVCARE), BC Cancer, and Vancouver General Hospital, University of British Columbia, Vancouver, Canada. 48

49. Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada. 49

50. Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota. 50

51. Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota. 51

52. EUTOPS Institute, University of Innsbruck, Innsbruck, Austria. 52

53. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. 53

54. Department of Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado. 54

55. Community Health Sciences, University of Calgary, Calgary, Canada. 55

56. Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 56

57. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 57

58. Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway. 58

59. Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California. 59

60. Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, Canada. 60

61. Division of Acute Disease Epidemiology, South Carolina Department of Health & Environmental Control, Columbia, South Carolina. 61

62. Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania. 62

63. Women’s Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania. 63

64. Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, California. 64

65. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 65

66. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. 66

67. Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom. 67

68. Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota. 68

Abstract

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Funder

National Health and Medical Research Council

National Cancer Institute

U.S. Army Medical Research and Development Command

Victorian Cancer Agency

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Krebsliga Schweiz

Swedish Cancer Foundation

HORIZON EUROPE European Research Council

Michael Smith Health Research BC

Janet D. Cottrelle Foundation

Foundation for Clinical-Experimental Cancer Research