Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer

Lydia Quaye; Jonathan Tyrer; Susan J Ramus; Honglin Song; Eva Wozniak; Richard A DiCioccio; Valerie McGuire; Estrid Høgdall; Claus Høgdall; Jan Blaakaer; Ellen L Goode; Joellen M Schildkraut; Douglas F Easton; Susanne Krüger-Kjaer; Alice S Whittemore; Simon A Gayther; Paul D P Pharoah

doi:10.1371/journal.pone.0005983

Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer

Lydia Quaye, Jonathan Tyrer, Susan J Ramus, Honglin Song, Eva Wozniak, Richard A DiCioccio, Valerie McGuire, Estrid Høgdall, Claus Høgdall, Jan Blaakaer, Ellen L Goode, Joellen M Schildkraut, Douglas F Easton, Susanne Krüger-Kjaer, Alice S Whittemore, Simon A Gayther, Paul D P Pharoah

35 Citations (Scopus)

Abstract

BACKGROUND: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. METHODS: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. RESULTS: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). CONCLUSION: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.

Original language	English
Journal	PLoS ONE
Volume	4
Issue number	6
Pages (from-to)	e5983
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0005983
Publication status	Published - 2009

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Quaye, L., Tyrer, J., Ramus, S. J., Song, H., Wozniak, E., DiCioccio, R. A., McGuire, V., Høgdall, E., Høgdall, C., Blaakaer, J., Goode, E. L., Schildkraut, J. M., Easton, D. F., Krüger-Kjaer, S., Whittemore, A. S., Gayther, S. A., & Pharoah, P. D. P. (2009). Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS ONE, 4(6), e5983. https://doi.org/10.1371/journal.pone.0005983

Quaye, L, Tyrer, J, Ramus, SJ, Song, H, Wozniak, E, DiCioccio, RA, McGuire, V, Høgdall, E , Høgdall, C, Blaakaer, J, Goode, EL, Schildkraut, JM, Easton, DF, Krüger-Kjaer, S, Whittemore, AS, Gayther, SA & Pharoah, PDP 2009, 'Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer', PLoS ONE, vol. 4, no. 6, pp. e5983. https://doi.org/10.1371/journal.pone.0005983

@article{30bfaa00689411df928f000ea68e967b,

title = "Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer",

abstract = "BACKGROUND: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. METHODS: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. RESULTS: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). CONCLUSION: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.",

author = "Lydia Quaye and Jonathan Tyrer and Ramus, {Susan J} and Honglin Song and Eva Wozniak and DiCioccio, {Richard A} and Valerie McGuire and Estrid H{\o}gdall and Claus H{\o}gdall and Jan Blaakaer and Goode, {Ellen L} and Schildkraut, {Joellen M} and Easton, {Douglas F} and Susanne Kr{\"u}ger-Kjaer and Whittemore, {Alice S} and Gayther, {Simon A} and Pharoah, {Paul D P}",

note = "Keywords: Adult; Aged; Aged, 80 and over; Case-Control Studies; Family Health; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Middle Aged; Neoplasm Invasiveness; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Risk",

year = "2009",

doi = "10.1371/journal.pone.0005983",

language = "English",

volume = "4",

pages = "e5983",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "6",

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TY - JOUR

T1 - Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer

AU - Quaye, Lydia

AU - Tyrer, Jonathan

AU - Ramus, Susan J

AU - Song, Honglin

AU - Wozniak, Eva

AU - DiCioccio, Richard A

AU - McGuire, Valerie

AU - Høgdall, Estrid

AU - Høgdall, Claus

AU - Blaakaer, Jan

AU - Goode, Ellen L

AU - Schildkraut, Joellen M

AU - Easton, Douglas F

AU - Krüger-Kjaer, Susanne

AU - Whittemore, Alice S

AU - Gayther, Simon A

AU - Pharoah, Paul D P

N1 - Keywords: Adult; Aged; Aged, 80 and over; Case-Control Studies; Family Health; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Middle Aged; Neoplasm Invasiveness; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Risk

PY - 2009

Y1 - 2009

N2 - BACKGROUND: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. METHODS: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. RESULTS: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). CONCLUSION: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.

AB - BACKGROUND: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. METHODS: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. RESULTS: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). CONCLUSION: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.

U2 - 10.1371/journal.pone.0005983

DO - 10.1371/journal.pone.0005983

M3 - Journal article

C2 - 19543528

SN - 1932-6203

VL - 4

SP - e5983

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 6

ER -

Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer

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