Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Denise G. O’Mahony; Susan J. Ramus; Melissa C. Southey; Nicola S. Meagher; Andreas Hadjisavvas; Esther M. John; Ute Hamann; Evgeny N. Imyanitov; Irene L. Andrulis; Priyanka Sharma; Mary B. Daly; Christopher R. Hake; Jeffrey N. Weitzel; Anna Jakubowska; Andrew K. Godwin; Adalgeir Arason; Anita Bane; Jacques Simard; Penny Soucy; Maria A. Caligo; Phuong L. Mai; Kathleen B.M. Claes; Manuel R. Teixeira; Wendy K. Chung; Conxi Lazaro; Peter J. Hulick; Amanda E. Toland; Inge Sokilde Pedersen; HEBON Investigators; Marian J.E. Mourits; Susan L. Neuhausen; Ana Vega; Miguel de la Hoya; Heli Nevanlinna; Mallika Dhawan; Valentina Zampiga; Rita Danesi; Liliana Varesco; Viviana Gismondi; Valerio Gaetano Vellone; Paul A. James; Ramunas Janavicius; Liene Nikitina-Zake; Finn Cilius Nielsen; Thomas van Overeem Hansen; Tanja Pejovic; Ake Borg; Johanna Rantala; Kenneth Offit; Marco Montagna; Katherine L. Nathanson; Susan M. Domchek; Ana Osorio; María J. García; Beth Y. Karlan; GEMO Study Collaborators; Fabienne Lesueur; Anna De Fazio; David Bowtell; AOCS Group; Anna De Fazio; Lesley McGuffog; Goska Leslie; Michael T. Parsons; Thilo Dörk; Lisa Marie Speith; Elizabeth Santana dos Santos; Alexandre André B.A. da Costa; Paolo Radice; Paolo Peterlongo; Laura Papi; Christoph Engel; Eric Hahnen; Rita K. Schmutzler; Barbara Wappenschmidt; Douglas F. Easton; Marc Tischkowitz; Christian F. Singer; Yen Yen Tan; Alice S. Whittemore; Weiva Sieh; James D. Brenton; Drakoulis Yannoukakos; Florentia Fostira; Irene Konstantopoulou; Jana Soukupova; Michal Vocka; CZECANCA Consortium; Georgia Chenevix-Trench; Paul D.P. Pharoah; Antonis C. Antoniou; David E. Goldgar; Amanda B. Spurdle; Kyriaki Michailidou; Miguel de la Hoya; Thomas van Overeem Hansen; Elizabeth Santana dos Santos; The Consortium of Investigators of Modifiers of BRCA1/2; Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium

doi:10.1038/s41416-023-02263-5

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Denise G. O’Mahony, Susan J. Ramus, Melissa C. Southey, Nicola S. Meagher, Andreas Hadjisavvas, Esther M. John, Ute Hamann, Evgeny N. Imyanitov, Irene L. Andrulis, Priyanka Sharma, Mary B. Daly, Christopher R. Hake, Jeffrey N. Weitzel, Anna Jakubowska, Andrew K. Godwin, Adalgeir Arason, Anita Bane, Jacques Simard, Penny Soucy, Maria A. CaligoPhuong L. Mai, Kathleen B.M. Claes, Manuel R. Teixeira, Wendy K. Chung, Conxi Lazaro, Peter J. Hulick, Amanda E. Toland, Inge Sokilde Pedersen, HEBON Investigators, Marian J.E. Mourits (Medlem af forfattergruppering), Susan L. Neuhausen, Ana Vega, Miguel de la Hoya, Heli Nevanlinna, Mallika Dhawan, Valentina Zampiga, Rita Danesi, Liliana Varesco, Viviana Gismondi, Valerio Gaetano Vellone, Paul A. James, Ramunas Janavicius, Liene Nikitina-Zake, Finn Cilius Nielsen, Thomas van Overeem Hansen, Tanja Pejovic, Ake Borg, Johanna Rantala, Kenneth Offit, Marco Montagna, Katherine L. Nathanson, Susan M. Domchek, Ana Osorio, María J. García, Beth Y. Karlan, GEMO Study Collaborators, Fabienne Lesueur (Medlem af forfattergruppering), Anna De Fazio, David Bowtell (Medlem af forfattergruppering), AOCS Group, Anna De Fazio (Medlem af forfattergruppering), Lesley McGuffog, Goska Leslie, Michael T. Parsons, Thilo Dörk, Lisa Marie Speith, Elizabeth Santana dos Santos, Alexandre André B.A. da Costa, Paolo Radice, Paolo Peterlongo, Laura Papi, Christoph Engel, Eric Hahnen, Rita K. Schmutzler, Barbara Wappenschmidt, Douglas F. Easton, Marc Tischkowitz, Christian F. Singer, Yen Yen Tan, Alice S. Whittemore, Weiva Sieh, James D. Brenton, Drakoulis Yannoukakos, Florentia Fostira, Irene Konstantopoulou, Jana Soukupova (Medlem af forfattergruppering), Michal Vocka (Medlem af forfattergruppering), CZECANCA Consortium, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, David E. Goldgar, Amanda B. Spurdle, Kyriaki Michailidou^*, Miguel de la Hoya, Thomas van Overeem Hansen, Elizabeth Santana dos Santos, The Consortium of Investigators of Modifiers of BRCA1/2, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium

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Abstract

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).

Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.

Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Originalsprog	Engelsk
Tidsskrift	British Journal of Cancer
Vol/bind	128
Udgave nummer	12
Sider (fra-til)	2283-2294
Antal sider	12
ISSN	0007-0920
DOI	https://doi.org/10.1038/s41416-023-02263-5
Status	Udgivet - 29 jun. 2023

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O’Mahony, D. G., Ramus, S. J., Southey, M. C., Meagher, N. S., Hadjisavvas, A., John, E. M., Hamann, U., Imyanitov, E. N., Andrulis, I. L., Sharma, P., Daly, M. B., Hake, C. R., Weitzel, J. N., Jakubowska, A., Godwin, A. K., Arason, A., Bane, A., Simard, J., Soucy, P., ... Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium (2023). Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2. British Journal of Cancer, 128(12), 2283-2294. Advance online publication. https://doi.org/10.1038/s41416-023-02263-5

@article{27de752de9ee49dcb2683c625ba13d89,

title = "Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2",

abstract = "Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.",

author = "O{\textquoteright}Mahony, {Denise G.} and Ramus, {Susan J.} and Southey, {Melissa C.} and Meagher, {Nicola S.} and Andreas Hadjisavvas and John, {Esther M.} and Ute Hamann and Imyanitov, {Evgeny N.} and Andrulis, {Irene L.} and Priyanka Sharma and Daly, {Mary B.} and Hake, {Christopher R.} and Weitzel, {Jeffrey N.} and Anna Jakubowska and Godwin, {Andrew K.} and Adalgeir Arason and Anita Bane and Jacques Simard and Penny Soucy and Caligo, {Maria A.} and Mai, {Phuong L.} and Claes, {Kathleen B.M.} and Teixeira, {Manuel R.} and Chung, {Wendy K.} and Conxi Lazaro and Hulick, {Peter J.} and Toland, {Amanda E.} and Pedersen, {Inge Sokilde} and {HEBON Investigators} and Mourits, {Marian J.E.} and Neuhausen, {Susan L.} and Ana Vega and {de la Hoya}, Miguel and Heli Nevanlinna and Mallika Dhawan and Valentina Zampiga and Rita Danesi and Liliana Varesco and Viviana Gismondi and Vellone, {Valerio Gaetano} and James, {Paul A.} and Ramunas Janavicius and Liene Nikitina-Zake and Nielsen, {Finn Cilius} and {van Overeem Hansen}, Thomas and Tanja Pejovic and Ake Borg and Johanna Rantala and Kenneth Offit and Marco Montagna and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Ana Osorio and Garc{\'i}a, {Mar{\'i}a J.} and Karlan, {Beth Y.} and {GEMO Study Collaborators} and Fabienne Lesueur and {De Fazio}, Anna and David Bowtell and {AOCS Group} and {De Fazio}, Anna and Lesley McGuffog and Goska Leslie and Parsons, {Michael T.} and Thilo D{\"o}rk and Speith, {Lisa Marie} and {dos Santos}, {Elizabeth Santana} and {da Costa}, {Alexandre Andr{\'e} B.A.} and Paolo Radice and Paolo Peterlongo and Laura Papi and Christoph Engel and Eric Hahnen and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Easton, {Douglas F.} and Marc Tischkowitz and Singer, {Christian F.} and Tan, {Yen Yen} and Whittemore, {Alice S.} and Weiva Sieh and Brenton, {James D.} and Drakoulis Yannoukakos and Florentia Fostira and Irene Konstantopoulou and Jana Soukupova and Michal Vocka and {CZECANCA Consortium} and Georgia Chenevix-Trench and Pharoah, {Paul D.P.} and Antoniou, {Antonis C.} and Goldgar, {David E.} and Spurdle, {Amanda B.} and Kyriaki Michailidou and {de la Hoya}, Miguel and {van Overeem Hansen}, Thomas and {dos Santos}, {Elizabeth Santana} and {The Consortium of Investigators of Modifiers of BRCA1/2} and {Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = jun,

day = "29",

doi = "10.1038/s41416-023-02263-5",

language = "English",

volume = "128",

pages = "2283--2294",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "12",

}

O’Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, HEBON Investigators, Mourits, MJE, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, García, MJ, Karlan, BY, GEMO Study Collaborators, Lesueur, F, De Fazio, A, Bowtell, D, AOCS Group, De Fazio, A, McGuffog, L, Leslie, G, Parsons, MT, Dörk, T, Speith, LM, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, CZECANCA Consortium, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, de la Hoya, M, van Overeem Hansen, T, dos Santos, ES, The Consortium of Investigators of Modifiers of BRCA1/2 & Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium 2023, 'Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2', British Journal of Cancer, bind 128, nr. 12, s. 2283-2294. https://doi.org/10.1038/s41416-023-02263-5

TY - JOUR

T1 - Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

AU - O’Mahony, Denise G.

AU - Ramus, Susan J.

AU - Southey, Melissa C.

AU - Meagher, Nicola S.

AU - Hadjisavvas, Andreas

AU - John, Esther M.

AU - Hamann, Ute

AU - Imyanitov, Evgeny N.

AU - Andrulis, Irene L.

AU - Sharma, Priyanka

AU - Daly, Mary B.

AU - Hake, Christopher R.

AU - Weitzel, Jeffrey N.

AU - Jakubowska, Anna

AU - Godwin, Andrew K.

AU - Arason, Adalgeir

AU - Bane, Anita

AU - Simard, Jacques

AU - Soucy, Penny

AU - Caligo, Maria A.

AU - Mai, Phuong L.

AU - Claes, Kathleen B.M.

AU - Teixeira, Manuel R.

AU - Chung, Wendy K.

AU - Lazaro, Conxi

AU - Hulick, Peter J.

AU - Toland, Amanda E.

AU - Pedersen, Inge Sokilde

AU - HEBON Investigators

AU - Neuhausen, Susan L.

AU - Vega, Ana

AU - de la Hoya, Miguel

AU - Nevanlinna, Heli

AU - Dhawan, Mallika

AU - Zampiga, Valentina

AU - Danesi, Rita

AU - Varesco, Liliana

AU - Gismondi, Viviana

AU - Vellone, Valerio Gaetano

AU - James, Paul A.

AU - Janavicius, Ramunas

AU - Nikitina-Zake, Liene

AU - Nielsen, Finn Cilius

AU - van Overeem Hansen, Thomas

AU - Pejovic, Tanja

AU - Borg, Ake

AU - Rantala, Johanna

AU - Offit, Kenneth

AU - Montagna, Marco

AU - Nathanson, Katherine L.

AU - Domchek, Susan M.

AU - Osorio, Ana

AU - García, María J.

AU - Karlan, Beth Y.

AU - GEMO Study Collaborators

AU - De Fazio, Anna

AU - AOCS Group

AU - McGuffog, Lesley

AU - Leslie, Goska

AU - Parsons, Michael T.

AU - Dörk, Thilo

AU - Speith, Lisa Marie

AU - dos Santos, Elizabeth Santana

AU - da Costa, Alexandre André B.A.

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Papi, Laura

AU - Engel, Christoph

AU - Hahnen, Eric

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Easton, Douglas F.

AU - Tischkowitz, Marc

AU - Singer, Christian F.

AU - Tan, Yen Yen

AU - Whittemore, Alice S.

AU - Sieh, Weiva

AU - Brenton, James D.

AU - Yannoukakos, Drakoulis

AU - Fostira, Florentia

AU - Konstantopoulou, Irene

AU - CZECANCA Consortium

AU - Chenevix-Trench, Georgia

AU - Pharoah, Paul D.P.

AU - Antoniou, Antonis C.

AU - Goldgar, David E.

AU - Spurdle, Amanda B.

AU - Michailidou, Kyriaki

AU - de la Hoya, Miguel

AU - van Overeem Hansen, Thomas

AU - dos Santos, Elizabeth Santana

AU - The Consortium of Investigators of Modifiers of BRCA1/2

AU - Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium

A2 - Mourits, Marian J.E.

A2 - Lesueur, Fabienne

A2 - Bowtell, David

A2 - De Fazio, Anna

A2 - Soukupova, Jana

A2 - Vocka, Michal

PY - 2023/6/29

Y1 - 2023/6/29

N2 - Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

AB - Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

UR - http://www.scopus.com/inward/record.url?scp=85153204607&partnerID=8YFLogxK

U2 - 10.1038/s41416-023-02263-5

DO - 10.1038/s41416-023-02263-5

M3 - Journal article

C2 - 37076566

AN - SCOPUS:85153204607

SN - 0007-0920

VL - 128

SP - 2283

EP - 2294

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 12

ER -

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

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