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

Denise G. O’Mahony; Susan J. Ramus; Melissa C. Southey; The Consortium of Investigators of Modifiers of BRCA1/2; Liene Nikitina-Zake; HEBON Investigators; GEMO Study Collaborators; AOCS Group; CZECANCA Consortium; 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, The Consortium of Investigators of Modifiers of BRCA1/2, Liene Nikitina-Zake (Member of the Working Group), HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium

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

6 Citations (Scopus)

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ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.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.

Original language	English
Pages (from-to)	2283-2294
Number of pages	12
Journal	British Journal of Cancer
Volume	128
Issue number	12
DOIs	https://doi.org/10.1038/s41416-023-02263-5
Publication status	Published - 29 Jun 2023
Externally published	Yes

Field of Science*

1.6 Biological sciences
3.1 Basic medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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O’Mahony, D. G., Ramus, S. J., Southey, M. C., The Consortium of Investigators of Modifiers of BRCA1/2, Nikitina-Zake, L., HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, & 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. https://doi.org/10.1038/s41416-023-02263-5

@article{94afffd1a9b6497c88b973a51415cfc0,

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 {The Consortium of Investigators of Modifiers of BRCA1/2} and Meagher, {Nicola S.} 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 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 Andreas Hadjisavvas and Kyriaki Michailidou and {HEBON Investigators} and {GEMO Study Collaborators} and {AOCS Group} and {CZECANCA Consortium} and {Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium}",

note = "Publisher Copyright: {\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",

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publisher = "Nature Publishing Group",

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O’Mahony, DG, Ramus, SJ, Southey, MC, The Consortium of Investigators of Modifiers of BRCA1/2, Nikitina-Zake, L, HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium & 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, vol. 128, no. 12, pp. 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 - The Consortium of Investigators of Modifiers of BRCA1/2

AU - Michailidou, Kyriaki

AU - HEBON Investigators

AU - GEMO Study Collaborators

AU - AOCS Group

AU - CZECANCA Consortium

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

A2 - Meagher, Nicola S.

A2 - John, Esther M.

A2 - Hamann, Ute

A2 - Imyanitov, Evgeny N.

A2 - Andrulis, Irene L.

A2 - Sharma, Priyanka

A2 - Daly, Mary B.

A2 - Hake, Christopher R.

A2 - Weitzel, Jeffrey N.

A2 - Jakubowska, Anna

A2 - Godwin, Andrew K.

A2 - Arason, Adalgeir

A2 - Bane, Anita

A2 - Simard, Jacques

A2 - Soucy, Penny

A2 - Caligo, Maria A.

A2 - Mai, Phuong L.

A2 - Claes, Kathleen B.M.

A2 - Teixeira, Manuel R.

A2 - Chung, Wendy K.

A2 - Lazaro, Conxi

A2 - Hulick, Peter J.

A2 - Toland, Amanda E.

A2 - Pedersen, Inge Sokilde

A2 - Mourits, Marian J.E.

A2 - Neuhausen, Susan L.

A2 - Vega, Ana

A2 - de la Hoya, Miguel

A2 - Nevanlinna, Heli

A2 - Dhawan, Mallika

A2 - Zampiga, Valentina

A2 - Danesi, Rita

A2 - Varesco, Liliana

A2 - Gismondi, Viviana

A2 - Vellone, Valerio Gaetano

A2 - James, Paul A.

A2 - Janavicius, Ramunas

A2 - Nikitina-Zake, Liene

A2 - Nielsen, Finn Cilius

A2 - van Overeem Hansen, Thomas

A2 - Pejovic, Tanja

A2 - Borg, Ake

A2 - Rantala, Johanna

A2 - Offit, Kenneth

A2 - Montagna, Marco

A2 - Nathanson, Katherine L.

A2 - Hadjisavvas, Andreas

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

UR - https://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:000989800600004

U2 - 10.1038/s41416-023-02263-5

DO - 10.1038/s41416-023-02263-5

M3 - 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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