<br>FOXJ1 蛋白表达增加与高级别浆液性卵巢癌总体生存率改善相关：一项卵巢肿瘤组织分析联盟研究,British Journal of Cancer

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FOXJ1 蛋白表达增加与高级别浆液性卵巢癌总体生存率改善相关：一项卵巢肿瘤组织分析联盟研究
British Journal of Cancer ( IF 6.4 ) Pub Date : 2022-11-02 , DOI: 10.1038/s41416-022-02014-y
Ashley Weir _{1,

2,

3} , Eun-Young Kang ₄ , Nicola S Meagher _{1,

2,

5} , Gregg S Nelson ₆ , Prafull Ghatage ₆ , Cheng-Han Lee ₇ , Marjorie J Riggan ₈ , Aleksandra Gentry-Maharaj ₉ , Andy Ryan _{9,

10} , Naveena Singh ₁₁ , Martin Widschwendter ₁₂ , Jennifer Alsop ₁₃ , Michael S Anglesio _{14,

15} , Matthias W Beckmann ₁₆ , Jessica Berger ₁₇ , Christiani Bisinotto ₁₈ , Jessica Boros _{19,

20,

21} , Alison H Brand _{20,

21} , James D Brenton ₂₂ , Angela Brooks-Wilson ₂₃ , Michael E Carney ₂₄ , Julie M Cunningham ₂₅ , Kara L Cushing-Haugen ₂₆ , Cezary Cybulski ₂₇ , Esther Elishaev ₂₈ , Ramona Erber ₂₉ , Sian Fereday _{30,

31} , Anna Fischer ₃₂ , Luis Paz-Ares _{33,

34} , Javier Gayarre ₃₅ , Blake C Gilks ₃₆ , Marcel Grube ₃₇ , Paul R Harnett _{21,

38} , Holly R Harris _{26,

39} , Arndt Hartmann ₂₉ , Alexander Hein ₁₆ , Joy Hendley ₃₀ , Brenda Y Hernandez ₄₀ , Sabine Heublein ₄₁ , Yajue Huang ₂₅ , Tomasz Huzarski _{27,

42} , Anna Jakubowska _{27,

43} , Mercedes Jimenez-Linan ₄₄ , Catherine J Kennedy _{19,

20,

21} , Felix K F Kommoss ₄₅ , Jennifer M Koziak ₄₆ , Bernhard Kraemer ₃₇ , Nhu D Le ₄₇ , Jaime Lesnock ₁₇ , Jenny Lester ₄₈ , Jan Lubiński ₂₇ , Janusz Menkiszak ₄₉ , Britta Ney ₃₂ , Alexander Olawaiye ₁₇ , Sandra Orsulic ₄₈ , Ana Osorio _{35,

50} , Luis Robles-Díaz ₅₁ , Matthias Ruebner ₁₆ , Mitul Shah ₁₃ , Raghwa Sharma ₅₂ , Yurii B Shvetsov ₄₀ , Helen Steed _{53,

54} , Aline Talhouk _{14,

15} , Sarah E Taylor ₁₇ , Nadia Traficante _{30,

31} , Robert A Vierkant ₅₅ , Chen Wang ₅₆ , Lynne R Wilkens ₄₀ , Stacey J Winham ₅₆ , Javier Benitez _{35,

50} , Andrew Berchuck ₈ , David D Bowtell _{30,

31} , Francisco J Candido Dos Reis ₁₈ , Linda S Cook _{57,

58} , Anna DeFazio _{5,

19,

20,

21} , , Jennifer A Doherty ₅₉ , Peter A Fasching ₁₆ , María J García ₆₀ , Ellen L Goode ₆₁ , Marc T Goodman ₆₂ , Jacek Gronwald ₂₇ , David G Huntsman _{14,

63} , Beth Y Karlan ₄₈ , Stefan Kommoss ₃₇ , Francesmary Modugno _{17,

64,

65} , Joellen M Schildkraut ₆₆ , Hans-Peter Sinn ₄₅ , Annette Staebler ₃₂ , Linda E Kelemen ₆₇ , Caroline E Ford _{1,

2,

68} , Usha Menon ₉ , Paul D P Pharoah _{13,

69} , Martin Köbel ₄ , Susan J Ramus _{1,

2}

Affiliation

School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia.
Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, AB, Canada.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
Women's Cancer, Institute for Women's Health, University College London, London, UK.
Department of Pathology, Barts Health National Health Service Trust, London, UK.
EUTOPS Institute, University of Innsbruck, Innsbruck, Austria.
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
The University of Sydney, Sydney, NSW, Australia.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany.
H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
University of Hawaii Cancer Center, Honolulu, HI, USA.
Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Genetics and Pathology, University of Zielona Gora, Zielona Gora, Poland.
Pomeranian Medical University, Independent Laboratory of Molecular Biology and Genetic Diagnostics, Szczecin, Poland.
Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Alberta Health Services-Cancer Care, Calgary, AB, Canada.
Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
Familial Cancer Unit and Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, NSW, Australia.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada.
Section of Gynecologic Oncology Surgery, North Zone, Alberta Health Services, Edmonton, AB, Canada.
Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA.
Community Health Sciences, University of Calgary, Calgary, AB, Canada.
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

背景

最近，我们发现，当按 101 基因 mRNA 表达预后特征进行分层时，输卵管卵巢高级别浆液性癌 (HGSC) 患者的 5 年生存率存在 > 60% 的差异。考虑到不同的患者结果，本研究旨在通过免疫组织化学将预后 mRNA 标记物转化为蛋白质表达测定，并验证它们在 HGSC 中的生存关联。

方法

根据高质量抗体、与蛋白质表达的相关性以及初步队列中免疫组织化学评分的变化，选择了两个预后基因FOXJ1和GMNN （分别为n = 134 和n = 80）。来自卵巢肿瘤组织分析联盟的组织微阵列上的 6434 个 (FOXJ1) 和 5470 个 (GMNN) 福尔马林固定、石蜡包埋的卵巢肿瘤（分别为 4634 和 4185 HGSC）进行了免疫组织化学染色和评分，然后进行单变量和多变量生存分析。

结果

与 mRNA 一致，FOXJ1 蛋白表达与 HGSC 患者总生存期改善呈线性增加关系。表达量 >50% 的女性具有最有利的结果（HR = 0.78，95% CI 0.67–0.91， p < 0.0001）。 GMNN 蛋白表达与 HSGC 患者的总体生存率没有显着相关。然而，GMNN 表达 >35% 的 HGSC 显示出更好结果的趋势，尽管这并不显着。

结论

我们为 FOXJ1 在 HGSC 中的预后价值提供了基础证据，通过免疫组织化学验证了先前基于 mRNA 的预后关联。

"点击查看英文标题和摘要"

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Background

Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.

Methods

Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.

Results

Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67–0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant.

Conclusion

We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

更新日期：2022-11-02

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