Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Shalaka S Hampras; Lara E Sucheston-Campbell; Rikki Cannioto; Jenny Chang-Claude; Francesmary Modugno; Thilo Doerk; Peter Hillemanns; Leah Preus; Keith L Knutson; Paul K Wallace; Chi-chen Hong; Grace Friel; Warren Davis; Mary Nesline; Celeste L Pearce; Linda E Kelemen; Marc T Goodman; Elisa V Bandera; Kathryn L Terry; Nils Schoof; Kevin H Eng; Alyssa I Clay; Prashant K Singh; Janine M Joseph; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Helen Baker; Yukie Bean; Matthias W Beckmann; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G Campbell; Karen Carty; Linda S Cook; Daniel W Cramer; Cezary Cybulski; Agnieszka Dansonka-Mieszkowska; Joe Dennis; Evelyn Despierre; Ed Dicks; Jennifer A Doherty; Andreas Du Bois; Matthias Durst; Doug Easton; Diana Eccles; Robert P Edwards; Arif B Ekici; Peter A Fasching; Brooke L Fridley; Yu-Tang Gao; Aleksandra Gentry-Maharaj; Graham Giles; Rosalind M Glasspool; Jacek Gronwald; Patricia Harrington; Philipp Harter; Hanis Nazihah Hasmad; Alexander Hein; Florian Heitz; Michelle A T Hildebrandt; Claus Hogdall; Estrid Hogdall; Satoyo Hosono; Edwin S Iversen; Anna Jakubowska; Allan Jensen; Bu-Tian Ji; Beth Y Karlan; Melissa Kellar; Joseph L Kelley; Lambertus A Kiemeney; Rüdiger Klapdor; Nonna Kolomeyevskaya; Camilla Krakstad; Susanne K Kjaer; Bridget Kruszka; Jolanta Kupryjanczyk; Diether Lambrechts; Sandrina Lambrechts; Nhu D Le; Alice W Lee; Shashikant Lele; Arto Leminen; Jenny Lester; Douglas A Levine; Dong Liang; Jolanta Lissowska; Song Liu; Karen Lu; Jan Lubinski; Lene Lundvall; Leon F A G Massuger; Keitaro Matsuo; Valeria McGuire; John R McLaughlin; Ian McNeish; Usha Menon; Joanna Moes-Sosnowska; Steven A Narod; Lotte Nedergaard; Heli Nevanlinna; Stefan Nickels; Sara H Olson; Irene Orlow; Rachel Palmieri Weber; James Paul; Tanja Pejovic; Liisa M Pelttari; Barbara Perkins; Jenny Permuth-Wey; Malcolm C Pike; Joanna Plisiecka-Halasa; Elizabeth M Poole; Harvey A Risch; Mary Anne Rossing; Joseph H Rothstein; Anja Rudolph; Ingo B Runnebaum; Iwona K Rzepecka; Helga B Salvesen; Eva Schernhammer; Kristina Schmitt; Ira Schwaab; Xiao-Ou Shu; Yurii B Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C Southey; Ingvild L Tangen; Soo-Hwang Teo; Pamela J Thompson; Agnieszka Timorek; Ya-Yu Tsai; Shelley S Tworoger; Jonathan Tyrer; Anna M van Altena; Ignace Vergote; Robert A Vierkant; Christine Walsh; Shan Wang-Gohrke; Nicolas Wentzensen; Alice S Whittemore; Kristine G Wicklund; Lynne R Wilkens; Anna H Wu; Xifeng Wu; Yin Ling Woo; Hannah Yang; Wei Zheng; Argyrios Ziogas; Simon A Gayther; Susan J Ramus; Thomas A Sellers; Joellen M Schildkraut; Catherine M Phelan; Andrew Berchuck; Georgia Chenevix-Trench; Julie M Cunningham; Paul Pharoah; Roberta B Ness; Kunle Odunsi; Ellen L Goode; Kirsten B Moysich

doi:10.18632/oncotarget.10215

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Shalaka S Hampras, Lara E Sucheston-Campbell, Rikki Cannioto, Jenny Chang-Claude, Francesmary Modugno, Thilo Doerk, Peter Hillemanns, Leah Preus, Keith L Knutson, Paul K Wallace, Chi-chen Hong, Grace Friel, Warren Davis, Mary Nesline, Celeste L Pearce, Linda E Kelemen, Marc T Goodman, Elisa V Bandera, Kathryn L Terry, Nils SchoofKevin H Eng, Alyssa I Clay, Prashant K Singh, Janine M Joseph, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Yukie Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G Campbell, Karen Carty, Linda S Cook, Daniel W Cramer, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Andreas Du Bois, Matthias Durst, Doug Easton, Diana Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham Giles, Rosalind M Glasspool, Jacek Gronwald, Patricia Harrington, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Claus Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Melissa Kellar, Joseph L Kelley, Lambertus A Kiemeney, Rüdiger Klapdor, Nonna Kolomeyevskaya, Camilla Krakstad, Susanne K Kjaer, Bridget Kruszka, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashikant Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Jolanta Lissowska, Song Liu, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valeria McGuire, John R McLaughlin, Ian McNeish, Usha Menon, Joanna Moes-Sosnowska, Steven A Narod, Lotte Nedergaard, Heli Nevanlinna, Stefan Nickels, Sara H Olson, Irene Orlow, Rachel Palmieri Weber, James Paul, Tanja Pejovic, Liisa M Pelttari, Barbara Perkins, Jenny Permuth-Wey, Malcolm C Pike, Joanna Plisiecka-Halasa, Elizabeth M Poole, Harvey A Risch, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Kristina Schmitt, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Ingvild L Tangen, Soo-Hwang Teo, Pamela J Thompson, Agnieszka Timorek, Ya-Yu Tsai, Shelley S Tworoger, Jonathan Tyrer, Anna M van Altena, Ignace Vergote, Robert A Vierkant, Christine Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Simon A Gayther, Susan J Ramus, Thomas A Sellers, Joellen M Schildkraut, Catherine M Phelan, Andrew Berchuck, Georgia Chenevix-Trench, Julie M Cunningham, Paul Pharoah, Roberta B Ness, Kunle Odunsi, Ellen L Goode, Kirsten B Moysich

Institut for Klinisk Medicin

3 Citationer (Scopus)

Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Originalsprog	Engelsk
Tidsskrift	OncoTarget
Vol/bind	7
Udgave nummer	43
Sider (fra-til)	69097-69110
Antal sider	14
ISSN	1949-2553
DOI	https://doi.org/10.18632/oncotarget.10215
Status	Udgivet - 2016

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10.18632/oncotarget.10215

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Hampras, S. S., Sucheston-Campbell, L. E., Cannioto, R., Chang-Claude, J., Modugno, F., Doerk, T., Hillemanns, P., Preus, L., Knutson, K. L., Wallace, P. K., Hong, C., Friel, G., Davis, W., Nesline, M., Pearce, C. L., Kelemen, L. E., Goodman, M. T., Bandera, E. V., Terry, K. L., ... Moysich, K. B. (2016). Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer. OncoTarget, 7(43), 69097-69110. https://doi.org/10.18632/oncotarget.10215

Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, AI, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, Du Bois, A, Durst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, G, Glasspool, RM, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, YL, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, P, Ness, RB, Odunsi, K, Goode, EL & Moysich, KB 2016, 'Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer', OncoTarget, bind 7, nr. 43, s. 69097-69110. https://doi.org/10.18632/oncotarget.10215

@article{0f0b4a02b2f641ecb9dbfca6c7089aa5,

title = "Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer",

abstract = "Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.",

keywords = "Journal Article",

author = "Hampras, {Shalaka S} and Sucheston-Campbell, {Lara E} and Rikki Cannioto and Jenny Chang-Claude and Francesmary Modugno and Thilo Doerk and Peter Hillemanns and Leah Preus and Knutson, {Keith L} and Wallace, {Paul K} and Chi-chen Hong and Grace Friel and Warren Davis and Mary Nesline and Pearce, {Celeste L} and Kelemen, {Linda E} and Goodman, {Marc T} and Bandera, {Elisa V} and Terry, {Kathryn L} and Nils Schoof and Eng, {Kevin H} and Clay, {Alyssa I} and Singh, {Prashant K} and Joseph, {Janine M} and Aben, {Katja K H} and Hoda Anton-Culver and Natalia Antonenkova and Helen Baker and Yukie Bean and Beckmann, {Matthias W} and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G} and Karen Carty and Cook, {Linda S} and Cramer, {Daniel W} and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Joe Dennis and Evelyn Despierre and Ed Dicks and Doherty, {Jennifer A} and {Du Bois}, Andreas and Matthias Durst and Doug Easton and Diana Eccles and Edwards, {Robert P} and Ekici, {Arif B} and Fasching, {Peter A} and Fridley, {Brooke L} and Yu-Tang Gao and Aleksandra Gentry-Maharaj and Graham Giles and Glasspool, {Rosalind M} and Jacek Gronwald and Patricia Harrington and Philipp Harter and Hasmad, {Hanis Nazihah} and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A T} and Claus Hogdall and Estrid Hogdall and Satoyo Hosono and Iversen, {Edwin S} and Anna Jakubowska and Allan Jensen and Bu-Tian Ji and Karlan, {Beth Y} and Melissa Kellar and Kelley, {Joseph L} and Kiemeney, {Lambertus A} and R{\"u}diger Klapdor and Nonna Kolomeyevskaya and Camilla Krakstad and Kjaer, {Susanne K} and Bridget Kruszka and Jolanta Kupryjanczyk and Diether Lambrechts and Sandrina Lambrechts and Le, {Nhu D} and Lee, {Alice W} and Shashikant Lele and Arto Leminen and Jenny Lester and Levine, {Douglas A} and Dong Liang and Jolanta Lissowska and Song Liu and Karen Lu and Jan Lubinski and Lene Lundvall and Massuger, {Leon F A G} and Keitaro Matsuo and Valeria McGuire and McLaughlin, {John R} and Ian McNeish and Usha Menon and Joanna Moes-Sosnowska and Narod, {Steven A} and Lotte Nedergaard and Heli Nevanlinna and Stefan Nickels and Olson, {Sara H} and Irene Orlow and Weber, {Rachel Palmieri} and James Paul and Tanja Pejovic and Pelttari, {Liisa M} and Barbara Perkins and Jenny Permuth-Wey and Pike, {Malcolm C} and Joanna Plisiecka-Halasa and Poole, {Elizabeth M} and Risch, {Harvey A} and Rossing, {Mary Anne} and Rothstein, {Joseph H} and Anja Rudolph and Runnebaum, {Ingo B} and Rzepecka, {Iwona K} and Salvesen, {Helga B} and Eva Schernhammer and Kristina Schmitt and Ira Schwaab and Xiao-Ou Shu and Shvetsov, {Yurii B} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Southey, {Melissa C} and Tangen, {Ingvild L} and Soo-Hwang Teo and Thompson, {Pamela J} and Agnieszka Timorek and Ya-Yu Tsai and Tworoger, {Shelley S} and Jonathan Tyrer and {van Altena}, {Anna M} and Ignace Vergote and Vierkant, {Robert A} and Christine Walsh and Shan Wang-Gohrke and Nicolas Wentzensen and Whittemore, {Alice S} and Wicklund, {Kristine G} and Wilkens, {Lynne R} and Wu, {Anna H} and Xifeng Wu and Woo, {Yin Ling} and Hannah Yang and Wei Zheng and Argyrios Ziogas and Gayther, {Simon A} and Ramus, {Susan J} and Sellers, {Thomas A} and Schildkraut, {Joellen M} and Phelan, {Catherine M} and Andrew Berchuck and Georgia Chenevix-Trench and Cunningham, {Julie M} and Paul Pharoah and Ness, {Roberta B} and Kunle Odunsi and Goode, {Ellen L} and Moysich, {Kirsten B}",

year = "2016",

doi = "10.18632/oncotarget.10215",

language = "English",

volume = "7",

pages = "69097--69110",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

number = "43",

}

TY - JOUR

T1 - Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

AU - Hampras, Shalaka S

AU - Sucheston-Campbell, Lara E

AU - Cannioto, Rikki

AU - Chang-Claude, Jenny

AU - Modugno, Francesmary

AU - Doerk, Thilo

AU - Hillemanns, Peter

AU - Preus, Leah

AU - Knutson, Keith L

AU - Wallace, Paul K

AU - Hong, Chi-chen

AU - Friel, Grace

AU - Davis, Warren

AU - Nesline, Mary

AU - Pearce, Celeste L

AU - Kelemen, Linda E

AU - Goodman, Marc T

AU - Bandera, Elisa V

AU - Terry, Kathryn L

AU - Schoof, Nils

AU - Eng, Kevin H

AU - Clay, Alyssa I

AU - Singh, Prashant K

AU - Joseph, Janine M

AU - Aben, Katja K H

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Baker, Helen

AU - Bean, Yukie

AU - Beckmann, Matthias W

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A

AU - Brooks-Wilson, Angela

AU - Bruinsma, Fiona

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Carty, Karen

AU - Cook, Linda S

AU - Cramer, Daniel W

AU - Cybulski, Cezary

AU - Dansonka-Mieszkowska, Agnieszka

AU - Dennis, Joe

AU - Despierre, Evelyn

AU - Dicks, Ed

AU - Doherty, Jennifer A

AU - Du Bois, Andreas

AU - Durst, Matthias

AU - Easton, Doug

AU - Eccles, Diana

AU - Edwards, Robert P

AU - Ekici, Arif B

AU - Fasching, Peter A

AU - Fridley, Brooke L

AU - Gao, Yu-Tang

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham

AU - Glasspool, Rosalind M

AU - Gronwald, Jacek

AU - Harrington, Patricia

AU - Harter, Philipp

AU - Hasmad, Hanis Nazihah

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A T

AU - Hogdall, Claus

AU - Hogdall, Estrid

AU - Hosono, Satoyo

AU - Iversen, Edwin S

AU - Jakubowska, Anna

AU - Jensen, Allan

AU - Ji, Bu-Tian

AU - Karlan, Beth Y

AU - Kellar, Melissa

AU - Kelley, Joseph L

AU - Kiemeney, Lambertus A

AU - Klapdor, Rüdiger

AU - Kolomeyevskaya, Nonna

AU - Krakstad, Camilla

AU - Kjaer, Susanne K

AU - Kruszka, Bridget

AU - Kupryjanczyk, Jolanta

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Le, Nhu D

AU - Lee, Alice W

AU - Lele, Shashikant

AU - Leminen, Arto

AU - Lester, Jenny

AU - Levine, Douglas A

AU - Liang, Dong

AU - Lissowska, Jolanta

AU - Liu, Song

AU - Lu, Karen

AU - Lubinski, Jan

AU - Lundvall, Lene

AU - Massuger, Leon F A G

AU - Matsuo, Keitaro

AU - McGuire, Valeria

AU - McLaughlin, John R

AU - McNeish, Ian

AU - Menon, Usha

AU - Moes-Sosnowska, Joanna

AU - Narod, Steven A

AU - Nedergaard, Lotte

AU - Nevanlinna, Heli

AU - Nickels, Stefan

AU - Olson, Sara H

AU - Orlow, Irene

AU - Weber, Rachel Palmieri

AU - Paul, James

AU - Pejovic, Tanja

AU - Pelttari, Liisa M

AU - Perkins, Barbara

AU - Permuth-Wey, Jenny

AU - Pike, Malcolm C

AU - Plisiecka-Halasa, Joanna

AU - Poole, Elizabeth M

AU - Risch, Harvey A

AU - Rossing, Mary Anne

AU - Rothstein, Joseph H

AU - Rudolph, Anja

AU - Runnebaum, Ingo B

AU - Rzepecka, Iwona K

AU - Salvesen, Helga B

AU - Schernhammer, Eva

AU - Schmitt, Kristina

AU - Schwaab, Ira

AU - Shu, Xiao-Ou

AU - Shvetsov, Yurii B

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Song, Honglin

AU - Southey, Melissa C

AU - Tangen, Ingvild L

AU - Teo, Soo-Hwang

AU - Thompson, Pamela J

AU - Timorek, Agnieszka

AU - Tsai, Ya-Yu

AU - Tworoger, Shelley S

AU - Tyrer, Jonathan

AU - van Altena, Anna M

AU - Vergote, Ignace

AU - Vierkant, Robert A

AU - Walsh, Christine

AU - Wang-Gohrke, Shan

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S

AU - Wicklund, Kristine G

AU - Wilkens, Lynne R

AU - Wu, Anna H

AU - Wu, Xifeng

AU - Woo, Yin Ling

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Gayther, Simon A

AU - Ramus, Susan J

AU - Sellers, Thomas A

AU - Schildkraut, Joellen M

AU - Phelan, Catherine M

AU - Berchuck, Andrew

AU - Chenevix-Trench, Georgia

AU - Cunningham, Julie M

AU - Pharoah, Paul

AU - Ness, Roberta B

AU - Odunsi, Kunle

AU - Goode, Ellen L

AU - Moysich, Kirsten B

PY - 2016

Y1 - 2016

N2 - Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

AB - Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

KW - Journal Article

U2 - 10.18632/oncotarget.10215

DO - 10.18632/oncotarget.10215

M3 - Journal article

C2 - 27533245

SN - 1949-2553

VL - 7

SP - 69097

EP - 69110

JO - Oncotarget

JF - Oncotarget

IS - 43

ER -

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

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