Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Jennifer B Permuth; Brett Reid; Madalene Earp; Y Ann Chen; Alvaro N A Monteiro; Zhihua Chen; Georgia Chenevix-Trench; Peter A Fasching; Matthias W Beckmann; Diether Lambrechts; Adriaan Vanderstichele; Els Van Niewenhuyse; Ignace Vergote; Mary Anne Rossing; Jennifer Anne Doherty; Jenny Chang-Claude; Kirsten Moysich; Kunle Odunsi; Marc T Goodman; Yurii B Shvetsov; Lynne R Wilkens; Pamela J Thompson; Thilo Dörk; Natalia Bogdanova; Ralf Butzow; Heli Nevanlinna; Liisa Pelttari; Arto Leminen; Francesmary Modugno; Robert P Edwards; Roberta B Ness; Joseph Kelley; Florian Heitz; Beth Karlan; Jenny Lester; Susanne K Kjaer; Allan Jensen; Graham Giles; Michelle Hildebrandt; Dong Liang; Karen H Lu; Xifeng Wu; Douglas A Levine; Maria Bisogna; Andrew Berchuck; Daniel W Cramer; Kathryn L Terry; Shelley S Tworoger; Estrid Hogdall; Claus Hogdall; AOCS Study Group

doi:10.18632/oncotarget.10546

Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Jennifer B Permuth, Brett Reid, Madalene Earp, Y Ann Chen, Alvaro N A Monteiro, Zhihua Chen, Georgia Chenevix-Trench, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, Adriaan Vanderstichele, Els Van Niewenhuyse, Ignace Vergote, Mary Anne Rossing, Jennifer Anne Doherty, Jenny Chang-Claude, Kirsten Moysich, Kunle Odunsi, Marc T Goodman, Yurii B ShvetsovLynne R Wilkens, Pamela J Thompson, Thilo Dörk, Natalia Bogdanova, Ralf Butzow, Heli Nevanlinna, Liisa Pelttari, Arto Leminen, Francesmary Modugno, Robert P Edwards, Roberta B Ness, Joseph Kelley, Florian Heitz, Beth Karlan, Jenny Lester, Susanne K Kjaer, Allan Jensen, Graham Giles, Michelle Hildebrandt, Dong Liang, Karen H Lu, Xifeng Wu, Douglas A Levine, Maria Bisogna, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Shelley S Tworoger, Estrid Hogdall, Claus Hogdall, AOCS Study Group

Department of Clinical Medicine

11 Citations (Scopus)

Abstract

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10^-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10^-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10^-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with P_AML=0.022 and P_SKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.

Original language	English
Journal	OncoTarget
Volume	7
Issue number	45
Pages (from-to)	72381-72394
Number of pages	14
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.10546
Publication status	Published - 8 Nov 2016

Keywords

Journal Article

UN SDGs

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

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10.18632/oncotarget.10546Licence: CC BY

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Permuth, J. B., Reid, B., Earp, M., Chen, Y. A., Monteiro, A. N. A., Chen, Z., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vanderstichele, A., Van Niewenhuyse, E., Vergote, I., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M. T., ... AOCS Study Group (2016). Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration. OncoTarget, 7(45), 72381-72394. https://doi.org/10.18632/oncotarget.10546

Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Dörk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, Jensen, A, Giles, G, Hildebrandt, M, Liang, D, Lu, KH, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Cramer, DW, Terry, KL, Tworoger, SS, Hogdall, E , Hogdall, C & AOCS Study Group 2016, 'Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration', OncoTarget, vol. 7, no. 45, pp. 72381-72394. https://doi.org/10.18632/oncotarget.10546

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abstract = "RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.",

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author = "Permuth, {Jennifer B} and Brett Reid and Madalene Earp and Chen, {Y Ann} and Monteiro, {Alvaro N A} and Zhihua Chen and Georgia Chenevix-Trench and Fasching, {Peter A} and Beckmann, {Matthias W} and Diether Lambrechts and Adriaan Vanderstichele and {Van Niewenhuyse}, Els and Ignace Vergote and Rossing, {Mary Anne} and Doherty, {Jennifer Anne} and Jenny Chang-Claude and Kirsten Moysich and Kunle Odunsi and Goodman, {Marc T} and Shvetsov, {Yurii B} and Wilkens, {Lynne R} and Thompson, {Pamela J} and Thilo D{\"o}rk and Natalia Bogdanova and Ralf Butzow and Heli Nevanlinna and Liisa Pelttari and Arto Leminen and Francesmary Modugno and Edwards, {Robert P} and Ness, {Roberta B} and Joseph Kelley and Florian Heitz and Beth Karlan and Jenny Lester and Kjaer, {Susanne K} and Allan Jensen and Graham Giles and Michelle Hildebrandt and Dong Liang and Lu, {Karen H} and Xifeng Wu and Levine, {Douglas A} and Maria Bisogna and Andrew Berchuck and Cramer, {Daniel W} and Terry, {Kathryn L} and Tworoger, {Shelley S} and Estrid Hogdall and Claus Hogdall and {AOCS Study Group}",

year = "2016",

month = nov,

day = "8",

doi = "10.18632/oncotarget.10546",

language = "English",

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T1 - Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility

T2 - results from a large-scale collaboration

AU - Permuth, Jennifer B

AU - Reid, Brett

AU - Earp, Madalene

AU - Chen, Y Ann

AU - Monteiro, Alvaro N A

AU - Chen, Zhihua

AU - Chenevix-Trench, Georgia

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Lambrechts, Diether

AU - Vanderstichele, Adriaan

AU - Van Niewenhuyse, Els

AU - Vergote, Ignace

AU - Rossing, Mary Anne

AU - Doherty, Jennifer Anne

AU - Chang-Claude, Jenny

AU - Moysich, Kirsten

AU - Odunsi, Kunle

AU - Goodman, Marc T

AU - Shvetsov, Yurii B

AU - Wilkens, Lynne R

AU - Thompson, Pamela J

AU - Dörk, Thilo

AU - Bogdanova, Natalia

AU - Butzow, Ralf

AU - Nevanlinna, Heli

AU - Pelttari, Liisa

AU - Leminen, Arto

AU - Modugno, Francesmary

AU - Edwards, Robert P

AU - Ness, Roberta B

AU - Kelley, Joseph

AU - Heitz, Florian

AU - Karlan, Beth

AU - Lester, Jenny

AU - Kjaer, Susanne K

AU - Jensen, Allan

AU - Giles, Graham

AU - Hildebrandt, Michelle

AU - Liang, Dong

AU - Lu, Karen H

AU - Wu, Xifeng

AU - Levine, Douglas A

AU - Bisogna, Maria

AU - Berchuck, Andrew

AU - Cramer, Daniel W

AU - Terry, Kathryn L

AU - Tworoger, Shelley S

AU - Hogdall, Estrid

AU - Hogdall, Claus

AU - AOCS Study Group

PY - 2016/11/8

Y1 - 2016/11/8

N2 - RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.

AB - RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.

KW - Journal Article

U2 - 10.18632/oncotarget.10546

DO - 10.18632/oncotarget.10546

M3 - Journal article

C2 - 27911851

SN - 1949-2553

VL - 7

SP - 72381

EP - 72394

JO - Oncotarget

JF - Oncotarget

IS - 45

ER -

Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Abstract

Keywords

UN SDGs

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