Publication

Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays

Bouwman, P., van der Heijden, I., van der Gulden, H., de Bruijn, R., Braspenning, M. E., Moghadasi, S., Wessels, L. F. A., Segers, K., Badoer, C., Vandernoot, I., Hilbert, P., Storm, K., Blaumeiser, B., Claes, K. B. M., Seneca, S., Michils, G., van den Ouweland, A., Collée, J. M., van der Stoep, N., Blok, M. J., Bleeker, F. E., Hogervorst, F. B. L., Mensenkamp, A. R., van der Hout, A. H., Oosterwijk, J. C., van der Luijt, R. B., Koudijs, M. J., Vreeswijk, M. P. G. & Jonkers, J., 16-Jun-2020, In : Clinical Cancer Research. 35 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Bouwman, P., van der Heijden, I., van der Gulden, H., de Bruijn, R., Braspenning, M. E., Moghadasi, S., Wessels, L. F. A., Segers, K., Badoer, C., Vandernoot, I., Hilbert, P., Storm, K., Blaumeiser, B., Claes, K. B. M., Seneca, S., Michils, G., van den Ouweland, A., Collée, J. M., van der Stoep, N., ... Jonkers, J. (2020). Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-20-0255

Author

Bouwman, Peter ; van der Heijden, Ingrid ; van der Gulden, Hanneke ; de Bruijn, Roebi ; Braspenning, Merel E ; Moghadasi, Setareh ; Wessels, Lodewyk F A ; Segers, Karin ; Badoer, Cindy ; Vandernoot, Isabelle ; Hilbert, Pascale ; Storm, Katrien ; Blaumeiser, Bettina ; Claes, Kathleen B M ; Seneca, Sara ; Michils, Geneviève ; van den Ouweland, Ans ; Collée, J Margriet ; van der Stoep, Nienke ; Blok, Marinus J ; Bleeker, Fonnet E ; Hogervorst, Frans B L ; Mensenkamp, Arjen R ; van der Hout, Annemarie H ; Oosterwijk, Jan C ; van der Luijt, Rob B ; Koudijs, Marco J ; Vreeswijk, Maaike P G ; Jonkers, Jos. / Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays. In: Clinical Cancer Research. 2020.

Harvard

Bouwman, P, van der Heijden, I, van der Gulden, H, de Bruijn, R, Braspenning, ME, Moghadasi, S, Wessels, LFA, Segers, K, Badoer, C, Vandernoot, I, Hilbert, P, Storm, K, Blaumeiser, B, Claes, KBM, Seneca, S, Michils, G, van den Ouweland, A, Collée, JM, van der Stoep, N, Blok, MJ, Bleeker, FE, Hogervorst, FBL, Mensenkamp, AR, van der Hout, AH, Oosterwijk, JC, van der Luijt, RB, Koudijs, MJ, Vreeswijk, MPG & Jonkers, J 2020, 'Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-20-0255

Standard

Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays. / Bouwman, Peter; van der Heijden, Ingrid; van der Gulden, Hanneke; de Bruijn, Roebi; Braspenning, Merel E; Moghadasi, Setareh; Wessels, Lodewyk F A; Segers, Karin; Badoer, Cindy; Vandernoot, Isabelle; Hilbert, Pascale; Storm, Katrien; Blaumeiser, Bettina; Claes, Kathleen B M; Seneca, Sara; Michils, Geneviève; van den Ouweland, Ans; Collée, J Margriet; van der Stoep, Nienke; Blok, Marinus J; Bleeker, Fonnet E; Hogervorst, Frans B L; Mensenkamp, Arjen R; van der Hout, Annemarie H; Oosterwijk, Jan C; van der Luijt, Rob B; Koudijs, Marco J; Vreeswijk, Maaike P G; Jonkers, Jos.

In: Clinical Cancer Research, 16.06.2020.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Bouwman P, van der Heijden I, van der Gulden H, de Bruijn R, Braspenning ME, Moghadasi S et al. Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays. Clinical Cancer Research. 2020 Jun 16. https://doi.org/10.1158/1078-0432.CCR-20-0255


BibTeX

@article{b31986b4a5784e35a35fad7b3bff5f08,
title = "Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays",
abstract = "PURPOSE: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway.EXPERIMENTAL DESIGN: 238 BRCA1 VUS - comprising most BRCA1 VUS known in the Netherlands and Belgium - were tested for their ability to complement Brca1 deficient mouse ES cells in HRR, using cisplatin and olaparib sensitivity assays and a DR-GFP HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families.RESULTS: All three assays showed 100% sensitivity and specificity (95% CI = 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of seven (likely) pathogenic variants.CONCLUSIONS: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.",
author = "Peter Bouwman and {van der Heijden}, Ingrid and {van der Gulden}, Hanneke and {de Bruijn}, Roebi and Braspenning, {Merel E} and Setareh Moghadasi and Wessels, {Lodewyk F A} and Karin Segers and Cindy Badoer and Isabelle Vandernoot and Pascale Hilbert and Katrien Storm and Bettina Blaumeiser and Claes, {Kathleen B M} and Sara Seneca and Genevi{\`e}ve Michils and {van den Ouweland}, Ans and Coll{\'e}e, {J Margriet} and {van der Stoep}, Nienke and Blok, {Marinus J} and Bleeker, {Fonnet E} and Hogervorst, {Frans B L} and Mensenkamp, {Arjen R} and {van der Hout}, {Annemarie H} and Oosterwijk, {Jan C} and {van der Luijt}, {Rob B} and Koudijs, {Marco J} and Vreeswijk, {Maaike P G} and Jos Jonkers",
note = "Copyright {\textcopyright}2020, American Association for Cancer Research.",
year = "2020",
month = jun,
day = "16",
doi = "10.1158/1078-0432.CCR-20-0255",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "AMER ASSOC CANCER RESEARCH",

}

RIS

TY - JOUR

T1 - Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays

AU - Bouwman, Peter

AU - van der Heijden, Ingrid

AU - van der Gulden, Hanneke

AU - de Bruijn, Roebi

AU - Braspenning, Merel E

AU - Moghadasi, Setareh

AU - Wessels, Lodewyk F A

AU - Segers, Karin

AU - Badoer, Cindy

AU - Vandernoot, Isabelle

AU - Hilbert, Pascale

AU - Storm, Katrien

AU - Blaumeiser, Bettina

AU - Claes, Kathleen B M

AU - Seneca, Sara

AU - Michils, Geneviève

AU - van den Ouweland, Ans

AU - Collée, J Margriet

AU - van der Stoep, Nienke

AU - Blok, Marinus J

AU - Bleeker, Fonnet E

AU - Hogervorst, Frans B L

AU - Mensenkamp, Arjen R

AU - van der Hout, Annemarie H

AU - Oosterwijk, Jan C

AU - van der Luijt, Rob B

AU - Koudijs, Marco J

AU - Vreeswijk, Maaike P G

AU - Jonkers, Jos

N1 - Copyright ©2020, American Association for Cancer Research.

PY - 2020/6/16

Y1 - 2020/6/16

N2 - PURPOSE: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway.EXPERIMENTAL DESIGN: 238 BRCA1 VUS - comprising most BRCA1 VUS known in the Netherlands and Belgium - were tested for their ability to complement Brca1 deficient mouse ES cells in HRR, using cisplatin and olaparib sensitivity assays and a DR-GFP HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families.RESULTS: All three assays showed 100% sensitivity and specificity (95% CI = 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of seven (likely) pathogenic variants.CONCLUSIONS: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.

AB - PURPOSE: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway.EXPERIMENTAL DESIGN: 238 BRCA1 VUS - comprising most BRCA1 VUS known in the Netherlands and Belgium - were tested for their ability to complement Brca1 deficient mouse ES cells in HRR, using cisplatin and olaparib sensitivity assays and a DR-GFP HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families.RESULTS: All three assays showed 100% sensitivity and specificity (95% CI = 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of seven (likely) pathogenic variants.CONCLUSIONS: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.

U2 - 10.1158/1078-0432.CCR-20-0255

DO - 10.1158/1078-0432.CCR-20-0255

M3 - Article

C2 - 32546644

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -

ID: 127956863