No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Douglas F Easton; Fabienne Lesueur; Brennan Decker; Kyriaki Michailidou; Jun Li; Jamie Allen; Craig Luccarini; Karen A Pooley; Mitul Shah; Manjeet K Bolla; Qin Wang; Joe Dennis; Jamil Ahmad; Ella R Thompson; Francesca Damiola; Maroulio Pertesi; Catherine Voegele; Noura Mebirouk; Nivonirina Robinot; Geoffroy Durand; Nathalie Forey; Robert N Luben; Shahana Ahmed; Kristiina Aittomäki; Hoda Anton-Culver; Volker Arndt; Caroline Baynes; Matthias W Beckman; Javier Benitez; David Van Den Berg; William J Blot; Natalia V Bogdanova; Stig E Bojesen; Hermann Brenner; Jenny Chang-Claude; Kee Seng Chia; Ji-Yeob Choi; Don M Conroy; Angela Cox; Simon S Cross; Kamila Czene; Hatef Darabi; Peter Devilee; Mikael Eriksson; Peter A Fasching; Jonine Figueroa; Henrik Flyger; Florentia Fostira; Montserrat García-Closas; Graham G Giles; Australian Ovarian Cancer Study Group

doi:10.1136/jmedgenet-2015-103529

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Douglas F Easton, Fabienne Lesueur, Brennan Decker, Kyriaki Michailidou, Jun Li, Jamie Allen, Craig Luccarini, Karen A Pooley, Mitul Shah, Manjeet K Bolla, Qin Wang, Joe Dennis, Jamil Ahmad, Ella R Thompson, Francesca Damiola, Maroulio Pertesi, Catherine Voegele, Noura Mebirouk, Nivonirina Robinot, Geoffroy DurandNathalie Forey, Robert N Luben, Shahana Ahmed, Kristiina Aittomäki, Hoda Anton-Culver, Volker Arndt, Caroline Baynes, Matthias W Beckman, Javier Benitez, David Van Den Berg, William J Blot, Natalia V Bogdanova, Stig E Bojesen, Hermann Brenner, Jenny Chang-Claude, Kee Seng Chia, Ji-Yeob Choi, Don M Conroy, Angela Cox, Simon S Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Mikael Eriksson, Peter A Fasching, Jonine Figueroa, Henrik Flyger, Florentia Fostira, Montserrat García-Closas, Graham G Giles, Australian Ovarian Cancer Study Group

Department of Clinical Medicine

68 Citations (Scopus)

Abstract

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.

METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.

RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).

CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Original language	English
Journal	Journal of Medical Genetics
Volume	53
Pages (from-to)	298-309
Number of pages	12
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2015-103529
Publication status	Published - 26 Feb 2016

Keywords

Journal Article

UN SDGs

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

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10.1136/jmedgenet-2015-103529

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Easton, D. F., Lesueur, F., Decker, B., Michailidou, K., Li, J., Allen, J., Luccarini, C., Pooley, K. A., Shah, M., Bolla, M. K., Wang, Q., Dennis, J., Ahmad, J., Thompson, E. R., Damiola, F., Pertesi, M., Voegele, C., Mebirouk, N., Robinot, N., ... Australian Ovarian Cancer Study Group (2016). No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. Journal of Medical Genetics, 53, 298-309. https://doi.org/10.1136/jmedgenet-2015-103529

Easton, DF, Lesueur, F, Decker, B, Michailidou, K, Li, J, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Dennis, J, Ahmad, J, Thompson, ER, Damiola, F, Pertesi, M, Voegele, C, Mebirouk, N, Robinot, N, Durand, G, Forey, N, Luben, RN, Ahmed, S, Aittomäki, K, Anton-Culver, H, Arndt, V, Baynes, C, Beckman, MW, Benitez, J, Van Den Berg, D, Blot, WJ, Bogdanova, NV, Bojesen, SE, Brenner, H, Chang-Claude, J, Chia, KS, Choi, J-Y, Conroy, DM, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Fostira, F, García-Closas, M, Giles, GG & Australian Ovarian Cancer Study Group 2016, 'No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing', Journal of Medical Genetics, vol. 53, pp. 298-309. https://doi.org/10.1136/jmedgenet-2015-103529

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title = "No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing",

abstract = "BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.",

keywords = "Journal Article",

author = "Easton, {Douglas F} and Fabienne Lesueur and Brennan Decker and Kyriaki Michailidou and Jun Li and Jamie Allen and Craig Luccarini and Pooley, {Karen A} and Mitul Shah and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Jamil Ahmad and Thompson, {Ella R} and Francesca Damiola and Maroulio Pertesi and Catherine Voegele and Noura Mebirouk and Nivonirina Robinot and Geoffroy Durand and Nathalie Forey and Luben, {Robert N} and Shahana Ahmed and Kristiina Aittom{\"a}ki and Hoda Anton-Culver and Volker Arndt and Caroline Baynes and Beckman, {Matthias W} and Javier Benitez and {Van Den Berg}, David and Blot, {William J} and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Hermann Brenner and Jenny Chang-Claude and Chia, {Kee Seng} and Ji-Yeob Choi and Conroy, {Don M} and Angela Cox and Cross, {Simon S} and Kamila Czene and Hatef Darabi and Peter Devilee and Mikael Eriksson and Fasching, {Peter A} and Jonine Figueroa and Henrik Flyger and Florentia Fostira and Montserrat Garc{\'i}a-Closas and Giles, {Graham G} and {Australian Ovarian Cancer Study Group}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

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day = "26",

doi = "10.1136/jmedgenet-2015-103529",

language = "English",

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TY - JOUR

T1 - No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk

T2 - implications for gene panel testing

AU - Easton, Douglas F

AU - Lesueur, Fabienne

AU - Decker, Brennan

AU - Michailidou, Kyriaki

AU - Li, Jun

AU - Allen, Jamie

AU - Luccarini, Craig

AU - Pooley, Karen A

AU - Shah, Mitul

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Ahmad, Jamil

AU - Thompson, Ella R

AU - Damiola, Francesca

AU - Pertesi, Maroulio

AU - Voegele, Catherine

AU - Mebirouk, Noura

AU - Robinot, Nivonirina

AU - Durand, Geoffroy

AU - Forey, Nathalie

AU - Luben, Robert N

AU - Ahmed, Shahana

AU - Aittomäki, Kristiina

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Baynes, Caroline

AU - Beckman, Matthias W

AU - Benitez, Javier

AU - Van Den Berg, David

AU - Blot, William J

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

AU - Chia, Kee Seng

AU - Choi, Ji-Yeob

AU - Conroy, Don M

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Devilee, Peter

AU - Eriksson, Mikael

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Fostira, Florentia

AU - García-Closas, Montserrat

AU - Giles, Graham G

AU - Australian Ovarian Cancer Study Group

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/2/26

Y1 - 2016/2/26

N2 - BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

AB - BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

KW - Journal Article

U2 - 10.1136/jmedgenet-2015-103529

DO - 10.1136/jmedgenet-2015-103529

M3 - Journal article

C2 - 26921362

SN - 0022-2593

VL - 53

SP - 298

EP - 309

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

ER -

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

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