Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes
IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characteriz...
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RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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RC0254 Neoplasms. Tumors. Oncology (including Cancer) Mavaddat, Nasim Dorling, Leila Carvalho, Sara Allen, Jamie Gonzalez-Neira, Anna Keeman, Renske Bolla, Manjeet K. Dennis, Joe Wang, Qin Ahearn, Thomas U. Andrulis, Irene L. Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Blomqvist, Carl Bogdanova, Natalia Bojesen, Stig E. Briceno, Ignacio Bruning, Thomas Camp, Nicola J. Campbell, Archie Castelao, Jose E. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Christiansen, Hans Czene, Kamila Dork, Thilo Eriksson, Mikael Evans, D. Gareth Fasching, Peter A. Figueroa, Jonine D. Flyger, Henrik Gabrielson, Marike Gago-Dominguez, Manuela Geisler, Jurgen Giles, Graham G. Guenel, Pascal Hadjisavvas, Andreas Hahnen, Eric Hall, Per Hamann, Ute Hartikainen, Jaana M. Hartman, Mikael Hoppe, Reiner Howell, Anthony Jakubowska, Anna Jung, Audrey Khusnutdinova, Elza K. Kristensen, Vessela N. Li, Jingmei Lim, Swee Ho Lindblom, Annika Loizidou, Maria A. Lophatananon, Artitaya Lubinski, Jan Madsen, Michael J. Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Mavroudis, Dimitrios Milne, Roger L. Mohd Taib, Nur Aishah Morra, Anna Muir, Kenneth Obi, Nadia Osorio, Ana Park-Simon, Tjoung-Won Peterlongo, Paolo Radice, Paolo Saloustros, Emmanouil Sawyer, Elinor J. Schmutzler, Rita K. Shah, Mitul Sim, Xueling Southey, Melissa C. Thorne, Heather Tomlinson, Ian Torres, Diana Truong, Therese Yip, Cheng Har Spurdle, Amanda B. Vreeswijk, Maaike P. G. Dunning, Alison M. Garcia-Closas, Montserrat Pharoah, Paul D. P. Kvist, Anders Muranen, Taru A. Nevanlinna, Heli Teo, Soo Hwang Devilee, Peter Schmidt, Marjanka K. Easton, Douglas F. Consortium, Breast Canc Assoc Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
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IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1(11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 95% CI, 3.17-12.12]; OR, 6.19 95% CI, 2.99-12.79]; and OR, 10.05 95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)(+)ERBB2(-) high-grade subtype (OR, 4.99; 95% CI. 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR(+)ERBB2(+) and HR(-)ERBB2(+) subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies. |
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Mavaddat, Nasim Dorling, Leila Carvalho, Sara Allen, Jamie Gonzalez-Neira, Anna Keeman, Renske Bolla, Manjeet K. Dennis, Joe Wang, Qin Ahearn, Thomas U. Andrulis, Irene L. Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Blomqvist, Carl Bogdanova, Natalia Bojesen, Stig E. Briceno, Ignacio Bruning, Thomas Camp, Nicola J. Campbell, Archie Castelao, Jose E. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Christiansen, Hans Czene, Kamila Dork, Thilo Eriksson, Mikael Evans, D. Gareth Fasching, Peter A. Figueroa, Jonine D. Flyger, Henrik Gabrielson, Marike Gago-Dominguez, Manuela Geisler, Jurgen Giles, Graham G. Guenel, Pascal Hadjisavvas, Andreas Hahnen, Eric Hall, Per Hamann, Ute Hartikainen, Jaana M. Hartman, Mikael Hoppe, Reiner Howell, Anthony Jakubowska, Anna Jung, Audrey Khusnutdinova, Elza K. Kristensen, Vessela N. Li, Jingmei Lim, Swee Ho Lindblom, Annika Loizidou, Maria A. Lophatananon, Artitaya Lubinski, Jan Madsen, Michael J. Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Mavroudis, Dimitrios Milne, Roger L. Mohd Taib, Nur Aishah Morra, Anna Muir, Kenneth Obi, Nadia Osorio, Ana Park-Simon, Tjoung-Won Peterlongo, Paolo Radice, Paolo Saloustros, Emmanouil Sawyer, Elinor J. Schmutzler, Rita K. Shah, Mitul Sim, Xueling Southey, Melissa C. Thorne, Heather Tomlinson, Ian Torres, Diana Truong, Therese Yip, Cheng Har Spurdle, Amanda B. Vreeswijk, Maaike P. G. Dunning, Alison M. Garcia-Closas, Montserrat Pharoah, Paul D. P. Kvist, Anders Muranen, Taru A. Nevanlinna, Heli Teo, Soo Hwang Devilee, Peter Schmidt, Marjanka K. Easton, Douglas F. Consortium, Breast Canc Assoc |
author_facet |
Mavaddat, Nasim Dorling, Leila Carvalho, Sara Allen, Jamie Gonzalez-Neira, Anna Keeman, Renske Bolla, Manjeet K. Dennis, Joe Wang, Qin Ahearn, Thomas U. Andrulis, Irene L. Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Blomqvist, Carl Bogdanova, Natalia Bojesen, Stig E. Briceno, Ignacio Bruning, Thomas Camp, Nicola J. Campbell, Archie Castelao, Jose E. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Christiansen, Hans Czene, Kamila Dork, Thilo Eriksson, Mikael Evans, D. Gareth Fasching, Peter A. Figueroa, Jonine D. Flyger, Henrik Gabrielson, Marike Gago-Dominguez, Manuela Geisler, Jurgen Giles, Graham G. Guenel, Pascal Hadjisavvas, Andreas Hahnen, Eric Hall, Per Hamann, Ute Hartikainen, Jaana M. Hartman, Mikael Hoppe, Reiner Howell, Anthony Jakubowska, Anna Jung, Audrey Khusnutdinova, Elza K. Kristensen, Vessela N. Li, Jingmei Lim, Swee Ho Lindblom, Annika Loizidou, Maria A. Lophatananon, Artitaya Lubinski, Jan Madsen, Michael J. Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Mavroudis, Dimitrios Milne, Roger L. Mohd Taib, Nur Aishah Morra, Anna Muir, Kenneth Obi, Nadia Osorio, Ana Park-Simon, Tjoung-Won Peterlongo, Paolo Radice, Paolo Saloustros, Emmanouil Sawyer, Elinor J. Schmutzler, Rita K. Shah, Mitul Sim, Xueling Southey, Melissa C. Thorne, Heather Tomlinson, Ian Torres, Diana Truong, Therese Yip, Cheng Har Spurdle, Amanda B. Vreeswijk, Maaike P. G. Dunning, Alison M. Garcia-Closas, Montserrat Pharoah, Paul D. P. Kvist, Anders Muranen, Taru A. Nevanlinna, Heli Teo, Soo Hwang Devilee, Peter Schmidt, Marjanka K. Easton, Douglas F. Consortium, Breast Canc Assoc |
author_sort |
Mavaddat, Nasim |
title |
Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
title_short |
Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
title_full |
Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
title_fullStr |
Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
title_full_unstemmed |
Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes |
title_sort |
pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes |
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Amer Medical Assoc |
publishDate |
2022 |
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http://eprints.um.edu.my/43061/ |
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1778161691103592448 |
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my.um.eprints.430612023-09-06T03:56:46Z http://eprints.um.edu.my/43061/ Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes Mavaddat, Nasim Dorling, Leila Carvalho, Sara Allen, Jamie Gonzalez-Neira, Anna Keeman, Renske Bolla, Manjeet K. Dennis, Joe Wang, Qin Ahearn, Thomas U. Andrulis, Irene L. Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Blomqvist, Carl Bogdanova, Natalia Bojesen, Stig E. Briceno, Ignacio Bruning, Thomas Camp, Nicola J. Campbell, Archie Castelao, Jose E. Chang-Claude, Jenny Chanock, Stephen J. Chenevix-Trench, Georgia Christiansen, Hans Czene, Kamila Dork, Thilo Eriksson, Mikael Evans, D. Gareth Fasching, Peter A. Figueroa, Jonine D. Flyger, Henrik Gabrielson, Marike Gago-Dominguez, Manuela Geisler, Jurgen Giles, Graham G. Guenel, Pascal Hadjisavvas, Andreas Hahnen, Eric Hall, Per Hamann, Ute Hartikainen, Jaana M. Hartman, Mikael Hoppe, Reiner Howell, Anthony Jakubowska, Anna Jung, Audrey Khusnutdinova, Elza K. Kristensen, Vessela N. Li, Jingmei Lim, Swee Ho Lindblom, Annika Loizidou, Maria A. Lophatananon, Artitaya Lubinski, Jan Madsen, Michael J. Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Mavroudis, Dimitrios Milne, Roger L. Mohd Taib, Nur Aishah Morra, Anna Muir, Kenneth Obi, Nadia Osorio, Ana Park-Simon, Tjoung-Won Peterlongo, Paolo Radice, Paolo Saloustros, Emmanouil Sawyer, Elinor J. Schmutzler, Rita K. Shah, Mitul Sim, Xueling Southey, Melissa C. Thorne, Heather Tomlinson, Ian Torres, Diana Truong, Therese Yip, Cheng Har Spurdle, Amanda B. Vreeswijk, Maaike P. G. Dunning, Alison M. Garcia-Closas, Montserrat Pharoah, Paul D. P. Kvist, Anders Muranen, Taru A. Nevanlinna, Heli Teo, Soo Hwang Devilee, Peter Schmidt, Marjanka K. Easton, Douglas F. Consortium, Breast Canc Assoc RC0254 Neoplasms. Tumors. Oncology (including Cancer) IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1(11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 95% CI, 3.17-12.12]; OR, 6.19 95% CI, 2.99-12.79]; and OR, 10.05 95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)(+)ERBB2(-) high-grade subtype (OR, 4.99; 95% CI. 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR(+)ERBB2(+) and HR(-)ERBB2(+) subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies. Amer Medical Assoc 2022-03 Article PeerReviewed Mavaddat, Nasim and Dorling, Leila and Carvalho, Sara and Allen, Jamie and Gonzalez-Neira, Anna and Keeman, Renske and Bolla, Manjeet K. and Dennis, Joe and Wang, Qin and Ahearn, Thomas U. and Andrulis, Irene L. and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Blomqvist, Carl and Bogdanova, Natalia and Bojesen, Stig E. and Briceno, Ignacio and Bruning, Thomas and Camp, Nicola J. and Campbell, Archie and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Chenevix-Trench, Georgia and Christiansen, Hans and Czene, Kamila and Dork, Thilo and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine D. and Flyger, Henrik and Gabrielson, Marike and Gago-Dominguez, Manuela and Geisler, Jurgen and Giles, Graham G. and Guenel, Pascal and Hadjisavvas, Andreas and Hahnen, Eric and Hall, Per and Hamann, Ute and Hartikainen, Jaana M. and Hartman, Mikael and Hoppe, Reiner and Howell, Anthony and Jakubowska, Anna and Jung, Audrey and Khusnutdinova, Elza K. and Kristensen, Vessela N. and Li, Jingmei and Lim, Swee Ho and Lindblom, Annika and Loizidou, Maria A. and Lophatananon, Artitaya and Lubinski, Jan and Madsen, Michael J. and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Mavroudis, Dimitrios and Milne, Roger L. and Mohd Taib, Nur Aishah and Morra, Anna and Muir, Kenneth and Obi, Nadia and Osorio, Ana and Park-Simon, Tjoung-Won and Peterlongo, Paolo and Radice, Paolo and Saloustros, Emmanouil and Sawyer, Elinor J. and Schmutzler, Rita K. and Shah, Mitul and Sim, Xueling and Southey, Melissa C. and Thorne, Heather and Tomlinson, Ian and Torres, Diana and Truong, Therese and Yip, Cheng Har and Spurdle, Amanda B. and Vreeswijk, Maaike P. G. and Dunning, Alison M. and Garcia-Closas, Montserrat and Pharoah, Paul D. P. and Kvist, Anders and Muranen, Taru A. and Nevanlinna, Heli and Teo, Soo Hwang and Devilee, Peter and Schmidt, Marjanka K. and Easton, Douglas F. and Consortium, Breast Canc Assoc (2022) Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes. Jama Oncology, 8 (3). DOI https://doi.org/10.1001/jamaoncol.2021.6744 <https://doi.org/10.1001/jamaoncol.2021.6744>. 10.1001/jamaoncol.2021.6744 |