A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

Emilia M. Pulver; Chirantani Mukherjee; Gerarda van de Kamp; Stefan J. Roobol; Magdalena B. Rother; Hanneke van der Gulden; Roebi de Bruijn; Maria Valeria Lattanzio; Eline van der Burg; Anne Paulien Drenth; Nicole S. Verkaik; Kerstin Hahn; Sjoerd Klarenbeek; Renske de Korte-Grimmerink; Marieke van de Ven; Colin E.J. Pritchard; Ivo J. Huijbers; Bing Xia; Dik C. van Gent; Jeroen Essers; Haico van Attikum; Arnab Ray Chaudhuri; Peter Bouwman; Jos Jonkers

doi:10.1158/0008-5472.CAN-21-1415

A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

Emilia M. Pulver, Chirantani Mukherjee, Gerarda van de Kamp, Stefan J. Roobol, Magdalena B. Rother, Hanneke van der Gulden, Roebi de Bruijn, Maria Valeria Lattanzio, Eline van der Burg, Anne Paulien Drenth, Nicole S. Verkaik, Kerstin Hahn, Sjoerd Klarenbeek, Renske de Korte-Grimmerink, Marieke van de Ven, Colin E.J. Pritchard, Ivo J. Huijbers, Bing Xia, Dik C. van Gent, Jeroen EssersHaico van Attikum, Arnab Ray Chaudhuri, Peter Bouwman^*, Jos Jonkers

^*Corresponding author for this work

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

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Abstract

The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.

Original language	English
Pages (from-to)	6171-6182
Number of pages	12
Journal	Cancer Research
Volume	81
Issue number	24
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-1415
Publication status	Published - 15 Dec 2021

Bibliographical note

Funding Information:
The authors thank Jinhyuk Bhin for his assistance with bioinformatics analyses. The authors thank the NKI animal laboratory facilities and pathology unit, the NKI genomics core facility, and the NKI bioimaging facility for expert technical support. This work was supported by grants from the Dutch Cancer Society (KWF; NKI 2015-7877 to P. Bouwman, J. Jonkers, and Maaike P.G. Vreeswijk; 11008/2017-1 to A. Ray Chaudhuri; and 12092/2018 to J. Essers); the Dutch Research Council (NWO; VIDI VI. 193.131 to A. Ray Chaudhuri; VICI 91814643 to J. Jonkers; and VICI VI.C.182.052 to H. van Attikum); Oncode Institute, which is partly financed by KWF, NWO research program Mosaic (grant 017.008.022 to J. Jonkers); the Lundbeck Foundation (grant R223-2016-956 to J. Jonkers, Claus Storgaard Sørensen, and Finn Cilius Nielsen); Technologie stichting STW (project number 13577 to D.C. van Gent and J. Essers); and the Swiss National Science Foundation to K. Hahn.

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© 2021 American Association for Cancer Research

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Pulver, E. M., Mukherjee, C., van de Kamp, G., Roobol, S. J., Rother, M. B., van der Gulden, H., de Bruijn, R., Lattanzio, M. V., van der Burg, E., Drenth, A. P., Verkaik, N. S., Hahn, K., Klarenbeek, S., de Korte-Grimmerink, R., van de Ven, M., Pritchard, C. E. J., Huijbers, I. J., Xia, B., van Gent, D. C., ... Jonkers, J. (2021). A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair. Cancer Research, 81(24), 6171-6182. https://doi.org/10.1158/0008-5472.CAN-21-1415

@article{507f33b2d65d4672b19cf89dc59b5679,

title = "A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair",

abstract = "The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.",

author = "Pulver, {Emilia M.} and Chirantani Mukherjee and {van de Kamp}, Gerarda and Roobol, {Stefan J.} and Rother, {Magdalena B.} and {van der Gulden}, Hanneke and {de Bruijn}, Roebi and Lattanzio, {Maria Valeria} and {van der Burg}, Eline and Drenth, {Anne Paulien} and Verkaik, {Nicole S.} and Kerstin Hahn and Sjoerd Klarenbeek and {de Korte-Grimmerink}, Renske and {van de Ven}, Marieke and Pritchard, {Colin E.J.} and Huijbers, {Ivo J.} and Bing Xia and {van Gent}, {Dik C.} and Jeroen Essers and {van Attikum}, Haico and Chaudhuri, {Arnab Ray} and Peter Bouwman and Jos Jonkers",

note = "Funding Information: The authors thank Jinhyuk Bhin for his assistance with bioinformatics analyses. The authors thank the NKI animal laboratory facilities and pathology unit, the NKI genomics core facility, and the NKI bioimaging facility for expert technical support. This work was supported by grants from the Dutch Cancer Society (KWF; NKI 2015-7877 to P. Bouwman, J. Jonkers, and Maaike P.G. Vreeswijk; 11008/2017-1 to A. Ray Chaudhuri; and 12092/2018 to J. Essers); the Dutch Research Council (NWO; VIDI VI. 193.131 to A. Ray Chaudhuri; VICI 91814643 to J. Jonkers; and VICI VI.C.182.052 to H. van Attikum); Oncode Institute, which is partly financed by KWF, NWO research program Mosaic (grant 017.008.022 to J. Jonkers); the Lundbeck Foundation (grant R223-2016-956 to J. Jonkers, Claus Storgaard S{\o}rensen, and Finn Cilius Nielsen); Technologie stichting STW (project number 13577 to D.C. van Gent and J. Essers); and the Swiss National Science Foundation to K. Hahn. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research",

year = "2021",

month = dec,

day = "15",

doi = "10.1158/0008-5472.CAN-21-1415",

language = "English",

volume = "81",

pages = "6171--6182",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "24",

}

Pulver, EM, Mukherjee, C, van de Kamp, G, Roobol, SJ, Rother, MB, van der Gulden, H, de Bruijn, R, Lattanzio, MV, van der Burg, E, Drenth, AP, Verkaik, NS, Hahn, K, Klarenbeek, S, de Korte-Grimmerink, R, van de Ven, M, Pritchard, CEJ, Huijbers, IJ, Xia, B, van Gent, DC, Essers, J, van Attikum, H, Chaudhuri, AR, Bouwman, P & Jonkers, J 2021, 'A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair', Cancer Research, vol. 81, no. 24, pp. 6171-6182. https://doi.org/10.1158/0008-5472.CAN-21-1415

A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair. / Pulver, Emilia M.; Mukherjee, Chirantani; van de Kamp, Gerarda et al.
In: Cancer Research, Vol. 81, No. 24, 15.12.2021, p. 6171-6182.

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

TY - JOUR

T1 - A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

AU - Pulver, Emilia M.

AU - Mukherjee, Chirantani

AU - van de Kamp, Gerarda

AU - Roobol, Stefan J.

AU - Rother, Magdalena B.

AU - van der Gulden, Hanneke

AU - de Bruijn, Roebi

AU - Lattanzio, Maria Valeria

AU - van der Burg, Eline

AU - Drenth, Anne Paulien

AU - Verkaik, Nicole S.

AU - Hahn, Kerstin

AU - Klarenbeek, Sjoerd

AU - de Korte-Grimmerink, Renske

AU - van de Ven, Marieke

AU - Pritchard, Colin E.J.

AU - Huijbers, Ivo J.

AU - Xia, Bing

AU - van Gent, Dik C.

AU - Essers, Jeroen

AU - van Attikum, Haico

AU - Chaudhuri, Arnab Ray

AU - Bouwman, Peter

AU - Jonkers, Jos

N1 - Funding Information: The authors thank Jinhyuk Bhin for his assistance with bioinformatics analyses. The authors thank the NKI animal laboratory facilities and pathology unit, the NKI genomics core facility, and the NKI bioimaging facility for expert technical support. This work was supported by grants from the Dutch Cancer Society (KWF; NKI 2015-7877 to P. Bouwman, J. Jonkers, and Maaike P.G. Vreeswijk; 11008/2017-1 to A. Ray Chaudhuri; and 12092/2018 to J. Essers); the Dutch Research Council (NWO; VIDI VI. 193.131 to A. Ray Chaudhuri; VICI 91814643 to J. Jonkers; and VICI VI.C.182.052 to H. van Attikum); Oncode Institute, which is partly financed by KWF, NWO research program Mosaic (grant 017.008.022 to J. Jonkers); the Lundbeck Foundation (grant R223-2016-956 to J. Jonkers, Claus Storgaard Sørensen, and Finn Cilius Nielsen); Technologie stichting STW (project number 13577 to D.C. van Gent and J. Essers); and the Swiss National Science Foundation to K. Hahn. Publisher Copyright: © 2021 American Association for Cancer Research

PY - 2021/12/15

Y1 - 2021/12/15

N2 - The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.

AB - The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.

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U2 - 10.1158/0008-5472.CAN-21-1415

DO - 10.1158/0008-5472.CAN-21-1415

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ER -

A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

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