CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AOCS Group; Eun-Young Kang; Ashley Weir; Nicola S Meagher; Kyo Farrington; Gregg S Nelson; Prafull Ghatage; Cheng-Han Lee; Marjorie J Riggan; Adelyn Bolithon; Gordana Popovic; Betty Leung; Katrina Tang; Neil Lambie; Joshua Millstein; Jennifer Alsop; Michael S Anglesio; Beyhan Ataseven; Ellen Barlow; Matthias W Beckmann; Jessica Berger; Christiani Bisinotto; Hans Bösmüller; Jessica Boros; Alison H Brand; Angela Brooks-Wilson; Sara Y Brucker; Michael E Carney; Yovanni Casablanca; Alicia Cazorla-Jiménez; Paul A Cohen; Thomas P Conrads; Linda S Cook; Penny Coulson; Madeleine Courtney-Brooks; Daniel W Cramer; Philip Crowe; Julie M Cunningham; Cezary Cybulski; Kathleen M Darcy; Mona A El-Bahrawy; Esther Elishaev; Ramona Erber; Rhonda Farrell; Sian Fereday; Anna Fischer; María J García; Simon A Gayther; Aleksandra Gentry-Maharaj; C Blake Gilks; Marcel Grube; Paul R Harnett; Shariska Petersen Harrington; Philipp Harter; Arndt Hartmann; Jonathan L Hecht; Sebastian Heikaus; Alexander Hein; Florian Heitz; Joy Hendley; Brenda Y Hernandez; Susanna Hernando Polo; Sabine Heublein; Akira Hirasawa; Estrid Høgdall; Claus K Høgdall; Hugo M Horlings; David G Huntsman; Tomasz Huzarski; Andrea Jewell; Mercedes Jimenez-Linan; Michael E Jones; Scott H Kaufmann; Catherine J Kennedy; Dineo Khabele; Felix K F Kommoss; Roy F P M Kruitwagen; Diether Lambrechts; Nhu D Le; Marcin Lener; Jenny Lester; Yee Leung; Anna Linder; Liselore Loverix; Jan Lubiński; Rashna Madan; G Larry Maxwell; Francesmary Modugno; Susan L Neuhausen; Alexander Olawaiye; Siel Olbrecht; Sandra Orsulic; José Palacios; Celeste Leigh Pearce; Malcolm C Pike; Carmel M Quinn; Ganendra Raj Mohan; Cristina Rodríguez-Antona; Matthias Ruebner; Andy Ryan; Stuart G Salfinger; Naoko Sasamoto; Joellen M Schildkraut; Minouk J Schoemaker; Mitul Shah; Raghwa Sharma; Yurii B Shvetsov; Naveena Singh; Gabe S Sonke; Linda Steele; Colin J R Stewart; Karin Sundfeldt; Anthony J Swerdlow; Aline Talhouk; Adeline Tan; Sarah E Taylor; Kathryn L Terry; Aleksandra Tołoczko; Nadia Traficante; Koen K Van de Vijver; Maaike A van der Aa; Toon Van Gorp; Els Van Nieuwenhuysen; Lilian van-Wagensveld; Ignace Vergote; Robert A Vierkant; Chen Wang; Lynne R Wilkens; Stacey J Winham; Anna H Wu; Javier Benitez; Andrew Berchuck; Francisco J Candido Dos Reis; Anna DeFazio; Peter A Fasching; Ellen L Goode; Marc T Goodman; Jacek Gronwald; Beth Y Karlan; Stefan Kommoss; Usha Menon; Hans-Peter Sinn; Annette Staebler; James D Brenton; David D Bowtell; Paul D P Pharoah; Susan J Ramus; Martin Köbel

doi:10.1002/cncr.34582

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AOCS Group, Eun-Young Kang, Ashley Weir, Nicola S Meagher, Kyo Farrington, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Adelyn Bolithon, Gordana Popovic, Betty Leung, Katrina Tang, Neil Lambie, Joshua Millstein, Jennifer Alsop, Michael S Anglesio, Beyhan Ataseven, Ellen Barlow, Matthias W BeckmannJessica Berger, Christiani Bisinotto, Hans Bösmüller, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Sara Y Brucker, Michael E Carney, Yovanni Casablanca, Alicia Cazorla-Jiménez, Paul A Cohen, Thomas P Conrads, Linda S Cook, Penny Coulson, Madeleine Courtney-Brooks, Daniel W Cramer, Philip Crowe, Julie M Cunningham, Cezary Cybulski, Kathleen M Darcy, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Rhonda Farrell, Sian Fereday, Anna Fischer, María J García, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Marcel Grube, Paul R Harnett, Shariska Petersen Harrington, Philipp Harter, Arndt Hartmann, Jonathan L Hecht, Sebastian Heikaus, Alexander Hein, Florian Heitz, Joy Hendley, Brenda Y Hernandez, Susanna Hernando Polo, Sabine Heublein, Akira Hirasawa, Estrid Høgdall, Claus K Høgdall, Hugo M Horlings, David G Huntsman, Tomasz Huzarski, Andrea Jewell, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Dineo Khabele, Felix K F Kommoss, Roy F P M Kruitwagen, Diether Lambrechts, Nhu D Le, Marcin Lener, Jenny Lester, Yee Leung, Anna Linder, Liselore Loverix, Jan Lubiński, Rashna Madan, G Larry Maxwell, Francesmary Modugno, Susan L Neuhausen, Alexander Olawaiye, Siel Olbrecht, Sandra Orsulic, José Palacios, Celeste Leigh Pearce, Malcolm C Pike, Carmel M Quinn, Ganendra Raj Mohan, Cristina Rodríguez-Antona, Matthias Ruebner, Andy Ryan, Stuart G Salfinger, Naoko Sasamoto, Joellen M Schildkraut, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Yurii B Shvetsov, Naveena Singh, Gabe S Sonke, Linda Steele, Colin J R Stewart, Karin Sundfeldt, Anthony J Swerdlow, Aline Talhouk, Adeline Tan, Sarah E Taylor, Kathryn L Terry, Aleksandra Tołoczko, Nadia Traficante, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Ignace Vergote, Robert A Vierkant, Chen Wang, Lynne R Wilkens, Stacey J Winham, Anna H Wu, Javier Benitez, Andrew Berchuck, Francisco J Candido Dos Reis, Anna DeFazio, Peter A Fasching, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Beth Y Karlan, Stefan Kommoss, Usha Menon, Hans-Peter Sinn, Annette Staebler, James D Brenton, David D Bowtell, Paul D P Pharoah, Susan J Ramus, Martin Köbel

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

6 Citations (Scopus)

Abstract

Background: CyclinE1 (CCNE1)is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma(HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 over-expression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐levelamplificationofCCNE1andCCNE1overexpression,as well as a combination of the two, are linked to shorter overall survival in HGSC.
Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.
Results: High‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18;95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.
Conclusion: This study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Original language	English
Pages (from-to)	697-713
Number of pages	17
Journal	Cancer
Volume	129
Issue number	5
Early online date	26 Dec 2022
DOIs	https://doi.org/10.1002/cncr.34582
Publication status	Published - 1 Mar 2023

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AOCS Group, Kang, E.-Y., Weir, A., Meagher, N. S., Farrington, K., Nelson, G. S., Ghatage, P., Lee, C.-H., Riggan, M. J., Bolithon, A., Popovic, G., Leung, B., Tang, K., Lambie, N., Millstein, J., Alsop, J., Anglesio, M. S., Ataseven, B., Barlow, E., ... Köbel, M. (2023). CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study. Cancer, 129(5), 697-713. https://doi.org/10.1002/cncr.34582

@article{0e98bb2776444163913e0aa57cbc189e,

title = "CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study",

abstract = "Background: CyclinE1 (CCNE1)is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma(HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 over-expression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐levelamplificationofCCNE1andCCNE1overexpression,as well as a combination of the two, are linked to shorter overall survival in HGSC.Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.Results: High‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18;95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.Conclusion: This study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.",

author = "{AOCS Group} and Eun-Young Kang and Ashley Weir and Meagher, {Nicola S} and Kyo Farrington and Nelson, {Gregg S} and Prafull Ghatage and Cheng-Han Lee and Riggan, {Marjorie J} and Adelyn Bolithon and Gordana Popovic and Betty Leung and Katrina Tang and Neil Lambie and Joshua Millstein and Jennifer Alsop and Anglesio, {Michael S} and Beyhan Ataseven and Ellen Barlow and Beckmann, {Matthias W} and Jessica Berger and Christiani Bisinotto and Hans B{\"o}sm{\"u}ller and Jessica Boros and Brand, {Alison H} and Angela Brooks-Wilson and Brucker, {Sara Y} and Carney, {Michael E} and Yovanni Casablanca and Alicia Cazorla-Jim{\'e}nez and Cohen, {Paul A} and Conrads, {Thomas P} and Cook, {Linda S} and Penny Coulson and Madeleine Courtney-Brooks and Cramer, {Daniel W} and Philip Crowe and Cunningham, {Julie M} and Cezary Cybulski and Darcy, {Kathleen M} and El-Bahrawy, {Mona A} and Esther Elishaev and Ramona Erber and Rhonda Farrell and Sian Fereday and Anna Fischer and Garc{\'i}a, {Mar{\'i}a J} and Gayther, {Simon A} and Aleksandra Gentry-Maharaj and Gilks, {C Blake} and Marcel Grube and Harnett, {Paul R} and Harrington, {Shariska Petersen} and Philipp Harter and Arndt Hartmann and Hecht, {Jonathan L} and Sebastian Heikaus and Alexander Hein and Florian Heitz and Joy Hendley and Hernandez, {Brenda Y} and Polo, {Susanna Hernando} and Sabine Heublein and Akira Hirasawa and Estrid H{\o}gdall and H{\o}gdall, {Claus K} and Horlings, {Hugo M} and Huntsman, {David G} and Tomasz Huzarski and Andrea Jewell and Mercedes Jimenez-Linan and Jones, {Michael E} and Kaufmann, {Scott H} and Kennedy, {Catherine J} and Dineo Khabele and Kommoss, {Felix K F} and Kruitwagen, {Roy F P M} and Diether Lambrechts and Le, {Nhu D} and Marcin Lener and Jenny Lester and Yee Leung and Anna Linder and Liselore Loverix and Jan Lubi{\'n}ski and Rashna Madan and Maxwell, {G Larry} and Francesmary Modugno and Neuhausen, {Susan L} and Alexander Olawaiye and Siel Olbrecht and Sandra Orsulic and Jos{\'e} Palacios and Pearce, {Celeste Leigh} and Pike, {Malcolm C} and Quinn, {Carmel M} and Mohan, {Ganendra Raj} and Cristina Rodr{\'i}guez-Antona and Matthias Ruebner and Andy Ryan and Salfinger, {Stuart G} and Naoko Sasamoto and Schildkraut, {Joellen M} and Schoemaker, {Minouk J} and Mitul Shah and Raghwa Sharma and Shvetsov, {Yurii B} and Naveena Singh and Sonke, {Gabe S} and Linda Steele and Stewart, {Colin J R} and Karin Sundfeldt and Swerdlow, {Anthony J} and Aline Talhouk and Adeline Tan and Taylor, {Sarah E} and Terry, {Kathryn L} and Aleksandra To{\l}oczko and Nadia Traficante and {Van de Vijver}, {Koen K} and {van der Aa}, {Maaike A} and {Van Gorp}, Toon and {Van Nieuwenhuysen}, Els and Lilian van-Wagensveld and Ignace Vergote and Vierkant, {Robert A} and Chen Wang and Wilkens, {Lynne R} and Winham, {Stacey J} and Wu, {Anna H} and Javier Benitez and Andrew Berchuck and {Candido Dos Reis}, {Francisco J} and Anna DeFazio and Fasching, {Peter A} and Goode, {Ellen L} and Goodman, {Marc T} and Jacek Gronwald and Karlan, {Beth Y} and Stefan Kommoss and Usha Menon and Hans-Peter Sinn and Annette Staebler and Brenton, {James D} and Bowtell, {David D} and Pharoah, {Paul D P} and Ramus, {Susan J} and Martin K{\"o}bel",

note = "{\textcopyright} 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.",

year = "2023",

month = mar,

day = "1",

doi = "10.1002/cncr.34582",

language = "English",

volume = "129",

pages = "697--713",

journal = "Cancer",

issn = "0008-543X",

publisher = "John Wiley & Sons",

number = "5",

}

AOCS Group, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Bösmüller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jiménez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, García, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Polo, SH, Heublein, S, Hirasawa, A, Høgdall, E, Høgdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubiński, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodríguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Tołoczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ & Köbel, M 2023, 'CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study', Cancer, vol. 129, no. 5, pp. 697-713. https://doi.org/10.1002/cncr.34582

TY - JOUR

T1 - CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

T2 - An Ovarian Tumor Tissue Analysis consortium study

AU - AOCS Group

AU - Kang, Eun-Young

AU - Weir, Ashley

AU - Meagher, Nicola S

AU - Farrington, Kyo

AU - Nelson, Gregg S

AU - Ghatage, Prafull

AU - Lee, Cheng-Han

AU - Riggan, Marjorie J

AU - Bolithon, Adelyn

AU - Popovic, Gordana

AU - Leung, Betty

AU - Tang, Katrina

AU - Lambie, Neil

AU - Millstein, Joshua

AU - Alsop, Jennifer

AU - Anglesio, Michael S

AU - Ataseven, Beyhan

AU - Barlow, Ellen

AU - Beckmann, Matthias W

AU - Berger, Jessica

AU - Bisinotto, Christiani

AU - Bösmüller, Hans

AU - Boros, Jessica

AU - Brand, Alison H

AU - Brooks-Wilson, Angela

AU - Brucker, Sara Y

AU - Carney, Michael E

AU - Casablanca, Yovanni

AU - Cazorla-Jiménez, Alicia

AU - Cohen, Paul A

AU - Conrads, Thomas P

AU - Cook, Linda S

AU - Coulson, Penny

AU - Courtney-Brooks, Madeleine

AU - Cramer, Daniel W

AU - Crowe, Philip

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - Darcy, Kathleen M

AU - El-Bahrawy, Mona A

AU - Elishaev, Esther

AU - Erber, Ramona

AU - Farrell, Rhonda

AU - Fereday, Sian

AU - Fischer, Anna

AU - García, María J

AU - Gayther, Simon A

AU - Gentry-Maharaj, Aleksandra

AU - Gilks, C Blake

AU - Grube, Marcel

AU - Harnett, Paul R

AU - Harrington, Shariska Petersen

AU - Harter, Philipp

AU - Hartmann, Arndt

AU - Hecht, Jonathan L

AU - Heikaus, Sebastian

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hendley, Joy

AU - Hernandez, Brenda Y

AU - Polo, Susanna Hernando

AU - Heublein, Sabine

AU - Hirasawa, Akira

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Horlings, Hugo M

AU - Huntsman, David G

AU - Huzarski, Tomasz

AU - Jewell, Andrea

AU - Jimenez-Linan, Mercedes

AU - Jones, Michael E

AU - Kaufmann, Scott H

AU - Kennedy, Catherine J

AU - Khabele, Dineo

AU - Kommoss, Felix K F

AU - Kruitwagen, Roy F P M

AU - Lambrechts, Diether

AU - Le, Nhu D

AU - Lener, Marcin

AU - Lester, Jenny

AU - Leung, Yee

AU - Linder, Anna

AU - Loverix, Liselore

AU - Lubiński, Jan

AU - Madan, Rashna

AU - Maxwell, G Larry

AU - Modugno, Francesmary

AU - Neuhausen, Susan L

AU - Olawaiye, Alexander

AU - Olbrecht, Siel

AU - Orsulic, Sandra

AU - Palacios, José

AU - Pearce, Celeste Leigh

AU - Pike, Malcolm C

AU - Quinn, Carmel M

AU - Mohan, Ganendra Raj

AU - Rodríguez-Antona, Cristina

AU - Ruebner, Matthias

AU - Ryan, Andy

AU - Salfinger, Stuart G

AU - Sasamoto, Naoko

AU - Schildkraut, Joellen M

AU - Schoemaker, Minouk J

AU - Shah, Mitul

AU - Sharma, Raghwa

AU - Shvetsov, Yurii B

AU - Singh, Naveena

AU - Sonke, Gabe S

AU - Steele, Linda

AU - Stewart, Colin J R

AU - Sundfeldt, Karin

AU - Swerdlow, Anthony J

AU - Talhouk, Aline

AU - Tan, Adeline

AU - Taylor, Sarah E

AU - Terry, Kathryn L

AU - Tołoczko, Aleksandra

AU - Traficante, Nadia

AU - Van de Vijver, Koen K

AU - van der Aa, Maaike A

AU - Van Gorp, Toon

AU - Van Nieuwenhuysen, Els

AU - van-Wagensveld, Lilian

AU - Vergote, Ignace

AU - Vierkant, Robert A

AU - Wang, Chen

AU - Wilkens, Lynne R

AU - Winham, Stacey J

AU - Wu, Anna H

AU - Benitez, Javier

AU - Berchuck, Andrew

AU - Candido Dos Reis, Francisco J

AU - DeFazio, Anna

AU - Fasching, Peter A

AU - Goode, Ellen L

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Karlan, Beth Y

AU - Kommoss, Stefan

AU - Menon, Usha

AU - Sinn, Hans-Peter

AU - Staebler, Annette

AU - Brenton, James D

AU - Bowtell, David D

AU - Pharoah, Paul D P

AU - Ramus, Susan J

AU - Köbel, Martin

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Background: CyclinE1 (CCNE1)is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma(HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 over-expression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐levelamplificationofCCNE1andCCNE1overexpression,as well as a combination of the two, are linked to shorter overall survival in HGSC.Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.Results: High‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18;95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.Conclusion: This study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

AB - Background: CyclinE1 (CCNE1)is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma(HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 over-expression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐levelamplificationofCCNE1andCCNE1overexpression,as well as a combination of the two, are linked to shorter overall survival in HGSC.Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.Results: High‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18;95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.Conclusion: This study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

U2 - 10.1002/cncr.34582

DO - 10.1002/cncr.34582

M3 - Article

C2 - 36572991

SN - 0008-543X

VL - 129

SP - 697

EP - 713

JO - Cancer

JF - Cancer

IS - 5

ER -

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

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