Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Stacey J Winham; Ailith Pirie; Yian Ann Chen; Melissa C Larson; Zachary C Fogarty; Madalene A Earp; Hoda Anton-Culver; Elisa V Bandera; Daniel W Cramer; Jennifer A Doherty; Marc T Goodman; Jacek Gronwald; Beth Y Karlan; Susanne K. Kjaer; Douglas A Levine; Usha Menon; Roberta B Ness; Celeste L Pearce; Tanja Pejovic; Mary Anne Rossing; Nicolas Wentzensen; Yukie T Bean; Maria Bisogna; Louise A Brinton; Michael E Carney; Julie M Cunningham; Cezary Cybulski; Anna deFazio; Ed M Dicks; Robert P Edwards; Simon A Gayther; Aleksandra Gentry-Maharaj; Martin Gore; Edwin S Iversen; Allan Jensen; Sharon E Johnatty; Jenny Lester; Hui-Yi Lin; Jolanta Lissowska; Jan Lubinski; Janusz Menkiszak; Francesmary Modugno; Kirsten B Moysich; Irene Orlow; Malcolm C Pike; Susan J Ramus; Honglin Song; Kathryn L Terry; Pamela J Thompson; Jonathan P Tyrer; David J Van Den Berg; Robert A Vierkant; Allison F Vitonis; Christine Walsh; Lynne R Wilkens; Anna H Wu; Hannah Yang; Argyrios Ziogas; Andrew Berchuck; Georgia Chenevix-Trench; Joellen M Schildkraut; Jennifer Permuth-Wey; Catherine M Phelan; Paul P D Pharoah; Brooke L Fridley; Thomas A Sellers; Ellen L Goode

doi:10.1158/1055-9965.epi-15-0240

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Stacey J Winham, Ailith Pirie, Yian Ann Chen, Melissa C Larson, Zachary C Fogarty, Madalene A Earp, Hoda Anton-Culver, Elisa V Bandera, Daniel W Cramer, Jennifer A Doherty, Marc T Goodman, Jacek Gronwald, Beth Y Karlan, Susanne K. Kjaer, Douglas A Levine, Usha Menon, Roberta B Ness, Celeste L Pearce, Tanja Pejovic, Mary Anne RossingNicolas Wentzensen, Yukie T Bean, Maria Bisogna, Louise A Brinton, Michael E Carney, Julie M Cunningham, Cezary Cybulski, Anna deFazio, Ed M Dicks, Robert P Edwards, Simon A Gayther, Aleksandra Gentry-Maharaj, Martin Gore, Edwin S Iversen, Allan Jensen, Sharon E Johnatty, Jenny Lester, Hui-Yi Lin, Jolanta Lissowska, Jan Lubinski, Janusz Menkiszak, Francesmary Modugno, Kirsten B Moysich, Irene Orlow, Malcolm C Pike, Susan J Ramus, Honglin Song, Kathryn L Terry, Pamela J Thompson, Jonathan P Tyrer, David J Van Den Berg, Robert A Vierkant, Allison F Vitonis, Christine Walsh, Lynne R Wilkens, Anna H Wu, Hannah Yang, Argyrios Ziogas, Andrew Berchuck, Georgia Chenevix-Trench, Joellen M Schildkraut, Jennifer Permuth-Wey, Catherine M Phelan, Paul P D Pharoah, Brooke L Fridley, Thomas A Sellers, Ellen L Goode

Department of Public Health

6 Citations (Scopus)

Abstract

Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independentEOCstudies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (P_meta=1.1E-6,HR_Set1=1.17,HR_Set2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (P_meta = 1.1E-6; P_corrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOCsurvival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54.

Original language	English
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	25
Issue number	3
Pages (from-to)	446-454
Number of pages	9
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.epi-15-0240
Publication status	Published - 2016

UN SDGs

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

Access to Document

10.1158/1055-9965.epi-15-0240

446.full.pdfFinal published version, 881 KB

Cite this

Winham, S. J., Pirie, A., Chen, Y. A., Larson, M. C., Fogarty, Z. C., Earp, M. A., Anton-Culver, H., Bandera, E. V., Cramer, D. W., Doherty, J. A., Goodman, M. T., Gronwald, J., Karlan, B. Y., Kjaer, S. K., Levine, D. A., Menon, U., Ness, R. B., Pearce, C. L., Pejovic, T., ... Goode, E. L. (2016). Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer. Cancer Epidemiology Biomarkers and Prevention, 25(3), 446-454. https://doi.org/10.1158/1055-9965.epi-15-0240

Winham, SJ, Pirie, A, Chen, YA, Larson, MC, Fogarty, ZC, Earp, MA, Anton-Culver, H, Bandera, EV, Cramer, DW, Doherty, JA, Goodman, MT, Gronwald, J, Karlan, BY, Kjaer, SK, Levine, DA, Menon, U, Ness, RB, Pearce, CL, Pejovic, T, Rossing, MA, Wentzensen, N, Bean, YT, Bisogna, M, Brinton, LA, Carney, ME, Cunningham, JM, Cybulski, C, deFazio, A, Dicks, EM, Edwards, RP, Gayther, SA, Gentry-Maharaj, A, Gore, M, Iversen, ES, Jensen, A, Johnatty, SE, Lester, J, Lin, H-Y, Lissowska, J, Lubinski, J, Menkiszak, J, Modugno, F, Moysich, KB, Orlow, I, Pike, MC, Ramus, SJ, Song, H, Terry, KL, Thompson, PJ, Tyrer, JP, Van Den Berg, DJ, Vierkant, RA, Vitonis, AF, Walsh, C, Wilkens, LR, Wu, AH, Yang, H, Ziogas, A, Berchuck, A, Chenevix-Trench, G, Schildkraut, JM, Permuth-Wey, J, Phelan, CM, Pharoah, PPD, Fridley, BL, Sellers, TA & Goode, EL 2016, 'Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer', Cancer Epidemiology Biomarkers and Prevention, vol. 25, no. 3, pp. 446-454. https://doi.org/10.1158/1055-9965.epi-15-0240

@article{2b1b4f9da41748db80de05d8ef393e5e,

title = "Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer",

abstract = "Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independentEOCstudies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOCsurvival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54.",

author = "Winham, {Stacey J} and Ailith Pirie and Chen, {Yian Ann} and Larson, {Melissa C} and Fogarty, {Zachary C} and Earp, {Madalene A} and Hoda Anton-Culver and Bandera, {Elisa V} and Cramer, {Daniel W} and Doherty, {Jennifer A} and Goodman, {Marc T} and Jacek Gronwald and Karlan, {Beth Y} and Kjaer, {Susanne K.} and Levine, {Douglas A} and Usha Menon and Ness, {Roberta B} and Pearce, {Celeste L} and Tanja Pejovic and Rossing, {Mary Anne} and Nicolas Wentzensen and Bean, {Yukie T} and Maria Bisogna and Brinton, {Louise A} and Carney, {Michael E} and Cunningham, {Julie M} and Cezary Cybulski and Anna deFazio and Dicks, {Ed M} and Edwards, {Robert P} and Gayther, {Simon A} and Aleksandra Gentry-Maharaj and Martin Gore and Iversen, {Edwin S} and Allan Jensen and Johnatty, {Sharon E} and Jenny Lester and Hui-Yi Lin and Jolanta Lissowska and Jan Lubinski and Janusz Menkiszak and Francesmary Modugno and Moysich, {Kirsten B} and Irene Orlow and Pike, {Malcolm C} and Ramus, {Susan J} and Honglin Song and Terry, {Kathryn L} and Thompson, {Pamela J} and Tyrer, {Jonathan P} and {Van Den Berg}, {David J} and Vierkant, {Robert A} and Vitonis, {Allison F} and Christine Walsh and Wilkens, {Lynne R} and Wu, {Anna H} and Hannah Yang and Argyrios Ziogas and Andrew Berchuck and Georgia Chenevix-Trench and Schildkraut, {Joellen M} and Jennifer Permuth-Wey and Phelan, {Catherine M} and Pharoah, {Paul P D} and Fridley, {Brooke L} and Sellers, {Thomas A} and Goode, {Ellen L}",

year = "2016",

doi = "10.1158/1055-9965.epi-15-0240",

language = "English",

volume = "25",

pages = "446--454",

journal = "Cancer Epidemiology, Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "3",

}

TY - JOUR

T1 - Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

AU - Winham, Stacey J

AU - Pirie, Ailith

AU - Chen, Yian Ann

AU - Larson, Melissa C

AU - Fogarty, Zachary C

AU - Earp, Madalene A

AU - Anton-Culver, Hoda

AU - Bandera, Elisa V

AU - Cramer, Daniel W

AU - Doherty, Jennifer A

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Karlan, Beth Y

AU - Kjaer, Susanne K.

AU - Levine, Douglas A

AU - Menon, Usha

AU - Ness, Roberta B

AU - Pearce, Celeste L

AU - Pejovic, Tanja

AU - Rossing, Mary Anne

AU - Wentzensen, Nicolas

AU - Bean, Yukie T

AU - Bisogna, Maria

AU - Brinton, Louise A

AU - Carney, Michael E

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - deFazio, Anna

AU - Dicks, Ed M

AU - Edwards, Robert P

AU - Gayther, Simon A

AU - Gentry-Maharaj, Aleksandra

AU - Gore, Martin

AU - Iversen, Edwin S

AU - Jensen, Allan

AU - Johnatty, Sharon E

AU - Lester, Jenny

AU - Lin, Hui-Yi

AU - Lissowska, Jolanta

AU - Lubinski, Jan

AU - Menkiszak, Janusz

AU - Modugno, Francesmary

AU - Moysich, Kirsten B

AU - Orlow, Irene

AU - Pike, Malcolm C

AU - Ramus, Susan J

AU - Song, Honglin

AU - Terry, Kathryn L

AU - Thompson, Pamela J

AU - Tyrer, Jonathan P

AU - Van Den Berg, David J

AU - Vierkant, Robert A

AU - Vitonis, Allison F

AU - Walsh, Christine

AU - Wilkens, Lynne R

AU - Wu, Anna H

AU - Yang, Hannah

AU - Ziogas, Argyrios

AU - Berchuck, Andrew

AU - Chenevix-Trench, Georgia

AU - Schildkraut, Joellen M

AU - Permuth-Wey, Jennifer

AU - Phelan, Catherine M

AU - Pharoah, Paul P D

AU - Fridley, Brooke L

AU - Sellers, Thomas A

AU - Goode, Ellen L

PY - 2016

Y1 - 2016

N2 - Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independentEOCstudies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOCsurvival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54.

AB - Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independentEOCstudies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOCsurvival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54.

U2 - 10.1158/1055-9965.epi-15-0240

DO - 10.1158/1055-9965.epi-15-0240

M3 - Journal article

C2 - 26747452

AN - SCOPUS:84961262486

SN - 1055-9965

VL - 25

SP - 446

EP - 454

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

IS - 3

ER -

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this