A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Wei-Yu Lin; Nicola J Camp; Lisa A Cannon-Albright; Kristina Allen-Brady; Sabapathy Balasubramanian; Malcolm W R Reed; John L Hopper; Carmel Apicella; Graham G Giles; Melissa C Southey; Roger L Milne; Jose I Arias-Pérez; Primitiva Menéndez-Rodríguez; Javier Benítez; Magdalena Grundmann; Natalia Dubrowinskaja; Tjoung-Won Park-Simon; Thilo Dörk; Montserrat Garcia-Closas; Jonine Figueroa; Mark Sherman; Jolanta Lissowska; Douglas F Easton; Alison M Dunning; Preetha Rajaraman; Alice J Sigurdson; Michele M Doody; Martha S Linet; Paul D Pharoah; Marjanka K Schmidt; Angela Cox

doi:10.1136/jmedgenet-2011-100018

A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Wei-Yu Lin, Nicola J Camp, Lisa A Cannon-Albright, Kristina Allen-Brady, Sabapathy Balasubramanian, Malcolm W R Reed, John L Hopper, Carmel Apicella, Graham G Giles, Melissa C Southey, Roger L Milne, Jose I Arias-Pérez, Primitiva Menéndez-Rodríguez, Javier Benítez, Magdalena Grundmann, Natalia Dubrowinskaja, Tjoung-Won Park-Simon, Thilo Dörk, Montserrat Garcia-Closas, Jonine FigueroaMark Sherman, Jolanta Lissowska, Douglas F Easton, Alison M Dunning, Preetha Rajaraman, Alice J Sigurdson, Michele M Doody, Martha S Linet, Paul D Pharoah, Marjanka K Schmidt, Angela Cox

Deanery of Molecular, Genetic and Population Health Sciences

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

Abstract / Description of output

BACKGROUND: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.

METHODS: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).

RESULTS: The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).

CONCLUSIONS: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

Original language	English
Pages (from-to)	477-84
Number of pages	8
Journal	Journal of Medical Genetics
Volume	48
Issue number	7
DOIs	https://doi.org/10.1136/jmedgenet-2011-100018
Publication status	Published - Jul 2011

Keywords / Materials (for Non-textual outputs)

Aged
Breast Neoplasms
Case-Control Studies
DNA-Binding Proteins
Female
Gene Expression Regulation, Neoplastic
Gene Frequency
Genetic Predisposition to Disease
Haplotypes
Humans
Inheritance Patterns
Middle Aged
Polymorphism, Single Nucleotide
Risk
Survival Analysis

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10.1136/jmedgenet-2011-100018

Cite this

Lin, W.-Y., Camp, N. J., Cannon-Albright, L. A., Allen-Brady, K., Balasubramanian, S., Reed, M. W. R., Hopper, J. L., Apicella, C., Giles, G. G., Southey, M. C., Milne, R. L., Arias-Pérez, J. I., Menéndez-Rodríguez, P., Benítez, J., Grundmann, M., Dubrowinskaja, N., Park-Simon, T.-W., Dörk, T., Garcia-Closas, M., ... Cox, A. (2011). A role for XRCC2 gene polymorphisms in breast cancer risk and survival. Journal of Medical Genetics, 48(7), 477-84. https://doi.org/10.1136/jmedgenet-2011-100018

@article{942b1f646807417ca1c6d2110813f6be,

title = "A role for XRCC2 gene polymorphisms in breast cancer risk and survival",

abstract = "BACKGROUND: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.METHODS: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).RESULTS: The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).CONCLUSIONS: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.",

keywords = "Aged, Breast Neoplasms, Case-Control Studies, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Inheritance Patterns, Middle Aged, Polymorphism, Single Nucleotide, Risk, Survival Analysis",

author = "Wei-Yu Lin and Camp, {Nicola J} and Cannon-Albright, {Lisa A} and Kristina Allen-Brady and Sabapathy Balasubramanian and Reed, {Malcolm W R} and Hopper, {John L} and Carmel Apicella and Giles, {Graham G} and Southey, {Melissa C} and Milne, {Roger L} and Arias-P{\'e}rez, {Jose I} and Primitiva Men{\'e}ndez-Rodr{\'i}guez and Javier Ben{\'i}tez and Magdalena Grundmann and Natalia Dubrowinskaja and Tjoung-Won Park-Simon and Thilo D{\"o}rk and Montserrat Garcia-Closas and Jonine Figueroa and Mark Sherman and Jolanta Lissowska and Easton, {Douglas F} and Dunning, {Alison M} and Preetha Rajaraman and Sigurdson, {Alice J} and Doody, {Michele M} and Linet, {Martha S} and Pharoah, {Paul D} and Schmidt, {Marjanka K} and Angela Cox",

year = "2011",

month = jul,

doi = "10.1136/jmedgenet-2011-100018",

language = "English",

volume = "48",

pages = "477--84",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BRITISH MED JOURNAL PUBL GROUP",

number = "7",

}

Lin, W-Y, Camp, NJ, Cannon-Albright, LA, Allen-Brady, K, Balasubramanian, S, Reed, MWR, Hopper, JL, Apicella, C, Giles, GG, Southey, MC, Milne, RL, Arias-Pérez, JI, Menéndez-Rodríguez, P, Benítez, J, Grundmann, M, Dubrowinskaja, N, Park-Simon, T-W, Dörk, T, Garcia-Closas, M, Figueroa, J, Sherman, M, Lissowska, J, Easton, DF, Dunning, AM, Rajaraman, P, Sigurdson, AJ, Doody, MM, Linet, MS, Pharoah, PD, Schmidt, MK & Cox, A 2011, 'A role for XRCC2 gene polymorphisms in breast cancer risk and survival', Journal of Medical Genetics, vol. 48, no. 7, pp. 477-84. https://doi.org/10.1136/jmedgenet-2011-100018

TY - JOUR

T1 - A role for XRCC2 gene polymorphisms in breast cancer risk and survival

AU - Lin, Wei-Yu

AU - Camp, Nicola J

AU - Cannon-Albright, Lisa A

AU - Allen-Brady, Kristina

AU - Balasubramanian, Sabapathy

AU - Reed, Malcolm W R

AU - Hopper, John L

AU - Apicella, Carmel

AU - Giles, Graham G

AU - Southey, Melissa C

AU - Milne, Roger L

AU - Arias-Pérez, Jose I

AU - Menéndez-Rodríguez, Primitiva

AU - Benítez, Javier

AU - Grundmann, Magdalena

AU - Dubrowinskaja, Natalia

AU - Park-Simon, Tjoung-Won

AU - Dörk, Thilo

AU - Garcia-Closas, Montserrat

AU - Figueroa, Jonine

AU - Sherman, Mark

AU - Lissowska, Jolanta

AU - Easton, Douglas F

AU - Dunning, Alison M

AU - Rajaraman, Preetha

AU - Sigurdson, Alice J

AU - Doody, Michele M

AU - Linet, Martha S

AU - Pharoah, Paul D

AU - Schmidt, Marjanka K

AU - Cox, Angela

PY - 2011/7

Y1 - 2011/7

N2 - BACKGROUND: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.METHODS: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).RESULTS: The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).CONCLUSIONS: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

AB - BACKGROUND: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.METHODS: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).RESULTS: The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).CONCLUSIONS: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

KW - Aged

KW - Breast Neoplasms

KW - Case-Control Studies

KW - DNA-Binding Proteins

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Inheritance Patterns

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Risk

KW - Survival Analysis

U2 - 10.1136/jmedgenet-2011-100018

DO - 10.1136/jmedgenet-2011-100018

M3 - Article

C2 - 21632523

SN - 0022-2593

VL - 48

SP - 477

EP - 484

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 7

ER -

A role for XRCC2 gene polymorphisms in breast cancer risk and survival

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Keywords / Materials (for Non-textual outputs)

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