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1. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author: Vergote, I., Ausems, M., Brasiuniene, B., Brenton, J., Büttner, R., Colombo, N., González-Martín, A., Harter, P., Lambrechts, D., Lorusso, D., Madry, R., Mirza, M.R., Pujol, P., Ray-Coquard, I., Abreu, M., Balboni, S., Banerjee, S., Barberis, M., Barretina Ginesta, M.P., Baurain, J.-F., Bignami, M., Bjorge, L., Blecharz, P., Bruchim, I., Capilna, M., Cerana, N., Cicchetti, A., Collins, D., Concin, N., D’Incalci, M., Davidson, B., de la Motte Rouge, T., De Iaco, P., Demirkiran, F., Denys, H., Doerk, T., Dorum, A., Ferrero, A., Fidalgo, A.P., Genuardi, M., Gladieff, L., Glasspool, R., Grimm, C., Gultekin, M., Hahnen, E., Hasenburg, A., Hegmane, A., Heinzelmann, V., Hogdall, E., Janavicius, R., Jarmalaite, S., Kalachand, R., Kaneva, R., Kilickap, S., Kocian, R., Kolencik, D., Kristeleit, R., Kryzhanivska, A., Leary, A., Lemley, B., Ligtenberg, M., López-Guerrero, J.A., Lord, C.J., Avall-Lundqvist, E., Maenpaa, J., Mahner, S., Marmé, F., Marth, C., McNeish, I., Merkelbach-Bruse, S., Mourits, M., Normanno, N., Oaknin, A., Ojamaa, K., Papdimitriou, C., Penault-Llorca, F., Perrone, A.M., Pignata, S., Pikarsky, E., Rouleau, E., Rubio, M., Sapino, A., Schmalfeldt, B., Sehouli, J., Shapira, R., Steffensen, K.D., Sukhin, V., Syrios, J., Szallasi, Z., Taskiran, C., Terzic, M., Tischkowitz, M., Toth, I., Van de Vijver, K., Vardar, M.A., Wasag, B., Wimberger, P., Witteveen, E., Brenton, J.D., and Ausems, M.G.E.M.
Published: 2022
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2. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP
Subjects: Epidemiology, Public Health and Health Services, Genetics
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

3. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

Author: Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I, Chenevix-Trench, G, Ovarian, CAC, Australian, OCSG, and Australian, CSOC
Abstract: We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
Published: 2010

4. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

Author: Pearce, CL, Near, AM, Van Den Berg, DJ, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, DiCioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JM, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, Cramer, DW, Terry, KL, Vitonis, AF, Titus-Ernstoff, L, Song, H, Pharoah, PDP, Spurdle, AB, Anton-Culver, H, Ziogas, A, Brewster, W, Galitovskiy, V, Chenevix-Trench, G, Australian Cancer Study, and Australian Ovarian Cancer Study Group
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, DNA Ligases, DNA-Binding Proteins, Risk Factors, Case-Control Studies, Cohort Studies, Genotype, Heterozygote, Homozygote, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Cytochrome P-450 CYP3A, DNA Ligase ATP, ovarian cancer, genetic susceptibility, oestrogen metabolism, CYP3A4, pooled-analyses, Polymorphism, Single Nucleotide, Ovarian Cancer, Genetics, Clinical Research, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract: The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
Published: 2009

5. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author: Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, Kobel, M, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, and Kobel, M
Abstract: BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023

6. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author: Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., Witteveen E., Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., and Witteveen E.
Abstract: Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR de
Published: 2022

7. Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment

Author: Leon-Castillo, A., Horeweg, N., Peters, E.E.M., Rutten, T., Haar, N. ter, Smit, V.T.H.B.M., Kroon, C.D., Boennelycke, M., Hogdall, E., Hogdall, C., Nout, R.R.A., Creutzberg, C.L., Ortoft, G., and Bosse, T.
Subjects: Lymphovascular space invasion, Obstetrics and Gynecology, Lymphadenectomy, Prognosis, Endometrial Neoplasms, Endometrial cancer, Oncology, Mutation, Biomarkers, Tumor, Humans, Lymph Node Excision, Female, Tumor Suppressor Protein p53, Molecular risk factors
Abstract: Introduction: The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment.Methods: DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis.Results: Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence.Conclusion: The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment.
Published: 2022

8. Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer

Author: Faber, M. T., Jensen, A., Frederiksen, K., Glud, E., Høgdall, E., Høgdall, C., Blaakær, J., and Kjær, S. K.
Published: 2013

9. Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

Author: Mogensen, M. B., Rossing, M., Østrup, O., Larsen, P. N., Heiberg Engel, P. J., Jørgensen, L. N., Hogdall, E. V., Eriksen, J., Ibsen, P., Jess, P., Grauslund, M., Nielsen, H. J., Nielsen, F. C., Vainer, B., and Osterlind, K.
Published: 2018
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10. Birth weight variants are associated with variable fetal intrauterine growth from 20 weeks of gestation

Author: Engelbrechtsen, L., Gybel-Brask, D., Mahendran, Y., Crusell, M., Hansen, T. H., Schnurr, T. M., Hogdall, E., Skibsted, L., Hansen, T., and Vestergaard, H.
Published: 2018
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11. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Author: Glubb D.M., Thompson D.J., Aben K.K.H., Alsulimani A., Amant F., Annibali D., Attia J., Barricarte A., Beckmann M.W., Berchuck A., Bermisheva M., Bernardini M.Q., Bischof K., Bjorge L., Bodelon C., Brand A.H., Brenton J.D., Brinton L.A., Bruinsma F., Buchanan D.D., Burghaus S., Butzow R., Cai H., Carney M.E., Chanock S.J., Chen C., Chen X.Q., Chen Z., Cook L.S., Cunningham J.M., De Vivo I., deFazio A., Doherty J.A., Dork T., du Bois A., Dunning A.M., Durst M., Edwards T., Edwards R.P., Ekici A.B., Ewing A., Fasching P.A., Ferguson S., Flanagan J.M., Fostira F., Fountzilas G., Friedenreich C.M., Gao B., Gaudet M.M., Gawelko J., Gentry-Maharaj A., Giles G.G., Glasspool R., Goodman M.T., Gronwald J., Harris H.R., Harter P., Hein A., Heitz F., Hildebrandt M.A.T., Hillemanns P., Hogdall E., Hogdall C.K., Holliday E.G., Huntsman D.G., Huzarski T., Jakubowska A., Jensen A., Jones M.E., Karlan B.Y., Karnezis A., Kelley J.L., Khusnutdinova E., Killeen J.L., Kjaer S.K., Klapdor R., Kobel M., Konopka B., Konstantopoulou I., Kopperud R.K., Koti M., Kraft P., Kupryjanczyk J., Lambrechts D., Larson M.C., Le Marchand L., Lele S., Lester J., Li A.J., Liang D., Liebrich C., Lipworth L., Lissowska J., Lu L., Lu K.H., Macciotta A., Mattiello A., May T., McAlpine J.N., McGuire V., McNeish I.A., Menon U., Modugno F., Moysich K.B., Nevanlinna H., Odunsi K., Olsson H., Orsulic S., Osorio A., Palli D., Park-Simon T.-W., Pearce C.L., Pejovic T., Permuth J.B., Podgorska A., Ramus S.J., Rebbeck T.R., Riggan M.J., Risch H.A., Rothstein J.H., Runnebaum I.B., Scott R.J., Sellers T.A., Senz J., Setiawan V.W., Siddiqui N., Sieh W., Spiewankiewicz B., Sutphen R., Swerdlow A.J., Szafron L.M., Teo S.H., Thompson P.J., Thomsen L.C.V., Titus L., Tone A., Tumino R., Turman C., Vanderstichele A., Edwards D.V., Vergote I., Vierkant R.A., Wang Z., Wang-Gohrke S., Webb P.M., White E., Whittemore A.S., Winham S.J., Wu X., Wu A.H., Yannoukakos D., Spurdle A.B., O'Mara T.A., Glubb D.M., Thompson D.J., Aben K.K.H., Alsulimani A., Amant F., Annibali D., Attia J., Barricarte A., Beckmann M.W., Berchuck A., Bermisheva M., Bernardini M.Q., Bischof K., Bjorge L., Bodelon C., Brand A.H., Brenton J.D., Brinton L.A., Bruinsma F., Buchanan D.D., Burghaus S., Butzow R., Cai H., Carney M.E., Chanock S.J., Chen C., Chen X.Q., Chen Z., Cook L.S., Cunningham J.M., De Vivo I., deFazio A., Doherty J.A., Dork T., du Bois A., Dunning A.M., Durst M., Edwards T., Edwards R.P., Ekici A.B., Ewing A., Fasching P.A., Ferguson S., Flanagan J.M., Fostira F., Fountzilas G., Friedenreich C.M., Gao B., Gaudet M.M., Gawelko J., Gentry-Maharaj A., Giles G.G., Glasspool R., Goodman M.T., Gronwald J., Harris H.R., Harter P., Hein A., Heitz F., Hildebrandt M.A.T., Hillemanns P., Hogdall E., Hogdall C.K., Holliday E.G., Huntsman D.G., Huzarski T., Jakubowska A., Jensen A., Jones M.E., Karlan B.Y., Karnezis A., Kelley J.L., Khusnutdinova E., Killeen J.L., Kjaer S.K., Klapdor R., Kobel M., Konopka B., Konstantopoulou I., Kopperud R.K., Koti M., Kraft P., Kupryjanczyk J., Lambrechts D., Larson M.C., Le Marchand L., Lele S., Lester J., Li A.J., Liang D., Liebrich C., Lipworth L., Lissowska J., Lu L., Lu K.H., Macciotta A., Mattiello A., May T., McAlpine J.N., McGuire V., McNeish I.A., Menon U., Modugno F., Moysich K.B., Nevanlinna H., Odunsi K., Olsson H., Orsulic S., Osorio A., Palli D., Park-Simon T.-W., Pearce C.L., Pejovic T., Permuth J.B., Podgorska A., Ramus S.J., Rebbeck T.R., Riggan M.J., Risch H.A., Rothstein J.H., Runnebaum I.B., Scott R.J., Sellers T.A., Senz J., Setiawan V.W., Siddiqui N., Sieh W., Spiewankiewicz B., Sutphen R., Swerdlow A.J., Szafron L.M., Teo S.H., Thompson P.J., Thomsen L.C.V., Titus L., Tone A., Tumino R., Turman C., Vanderstichele A., Edwards D.V., Vergote I., Vierkant R.A., Wang Z., Wang-Gohrke S., Webb P.M., White E., Whittemore A.S., Winham S.J., Wu X., Wu A.H., Yannoukakos D., Spurdle A.B., and O'Mara T.A.
Abstract: BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHOD(S): Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULT(S): Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 x 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 x 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 x 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSION(S): Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.Copyright ©2020 American Association for Cancer Research.
Published: 2022

12. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

13. Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author: Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, Ramus, SJ, Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, and Ramus, SJ
Abstract: PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
Published: 2022

14. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer

Author: Schou, J.V., Larsen, F.O., Rasch, L., Linnemann, D., Langhoff, J., Høgdall, E., Nielsen, D.L., Vistisen, K., Fromm, A., and Jensen, B.V.
Published: 2012
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15. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author: Quinn, MCJ, McCue, K, Shi, W, Johnatty, SE, Beesley, J, Civitarese, A, O'Mara, TA, Glubb, DM, Tyrer, JP, Armasu, SM, Ong, J-S, Gharahkhani, P, Lu, Y, Gao, B, Patch, A-M, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Doerk, T, Duerst, M, Modugno, F, Moysich, K, du Bois, A, Pfisterer, J, Bauman, K, Karlan, BY, Lester, J, Cunningham, JM, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Hogdall, CK, Hogdall, E, Schildkraut, JM, Riggan, MJ, Berchuck, A, Cramer, DW, Terry, KL, Bjorge, L, Webb, PM, Friedlander, M, Pejovic, T, Moffitt, M, Glasspool, R, May, T, Ene, GE, Huntsman, DG, Woo, M, Carney, ME, Hinsley, S, Heitz, F, Fereday, S, Kennedy, CJ, Edwards, SL, Winham, SJ, deFazio, A, Pharoah, PDP, Goode, EL, MacGregor, S, Chenevix-Trench, G, Quinn, MCJ, McCue, K, Shi, W, Johnatty, SE, Beesley, J, Civitarese, A, O'Mara, TA, Glubb, DM, Tyrer, JP, Armasu, SM, Ong, J-S, Gharahkhani, P, Lu, Y, Gao, B, Patch, A-M, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Doerk, T, Duerst, M, Modugno, F, Moysich, K, du Bois, A, Pfisterer, J, Bauman, K, Karlan, BY, Lester, J, Cunningham, JM, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Hogdall, CK, Hogdall, E, Schildkraut, JM, Riggan, MJ, Berchuck, A, Cramer, DW, Terry, KL, Bjorge, L, Webb, PM, Friedlander, M, Pejovic, T, Moffitt, M, Glasspool, R, May, T, Ene, GE, Huntsman, DG, Woo, M, Carney, ME, Hinsley, S, Heitz, F, Fereday, S, Kennedy, CJ, Edwards, SL, Winham, SJ, deFazio, A, Pharoah, PDP, Goode, EL, MacGregor, S, and Chenevix-Trench, G
Abstract: BACKGROUND: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. METHODS: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. RESULTS: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. CONCLUSIONS: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. IMPACT: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.
Published: 2021

16. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Author: Song, H, Dicks, EM, Tyrer, J, Intermaggio, M, Chenevix-Trench, G, Bowtell, DD, Traficante, N, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, N, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Kruger Kjaer, S, Hogdall, E, Campbell, IG, Lazaro, C, Pujara, MA, Cunningham, J, Vierkant, R, Winham, SJ, Hildebrandt, M, Huff, C, Li, D, Wu, X, Yu, Y, Permuth, JB, Levine, DA, Schildkraut, JM, Riggan, MJ, Berchuck, A, Webb, PM, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Alsop, J, Harrington, P, Chan, I, Menon, U, Pearce, CL, Wu, AH, de Fazio, A, Kennedy, CJ, Goode, E, Ramus, S, Gayther, S, Pharoah, P, Song, H, Dicks, EM, Tyrer, J, Intermaggio, M, Chenevix-Trench, G, Bowtell, DD, Traficante, N, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, N, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Kruger Kjaer, S, Hogdall, E, Campbell, IG, Lazaro, C, Pujara, MA, Cunningham, J, Vierkant, R, Winham, SJ, Hildebrandt, M, Huff, C, Li, D, Wu, X, Yu, Y, Permuth, JB, Levine, DA, Schildkraut, JM, Riggan, MJ, Berchuck, A, Webb, PM, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Alsop, J, Harrington, P, Chan, I, Menon, U, Pearce, CL, Wu, AH, de Fazio, A, Kennedy, CJ, Goode, E, Ramus, S, Gayther, S, and Pharoah, P
Abstract: PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
Published: 2021

17. PD-001 Total cell-free DNA level in plasma as strong prognostic marker in metastatic colorectal cancer

Author: Spindler, K.-L., Demuth, C., Soerensen, B., Johansen, J., Nielsen, D., Pallisgaard, N., Høgdall, E., Pfeiffer, P., Yilmaz, M., and Jensen, B.
Published: 2016
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18. The relation of germ cells per tubule in testes, serum inhibin B and FSH in cryptorchid boys

Author: Cortes, D., Thorup, J., Hogdall, E., Norgaard-Pedersen, B., Petersen, B. L., and Hogdall, C.
Published: 2007
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19. Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D

Author: Yang, X, Song, H, Leslie, G, Engel, C, Hahnen, E, Auber, B, Horvath, J, Kast, K, Niederacher, D, Turnbull, C, Houlston, R, Hanson, H, Loveday, C, Dolinsky, JS, LaDuca, H, Ramus, SJ, Menon, U, Rosenthal, AN, Jacobs, I, Gayther, SA, Dicks, E, Nevanlinna, H, Aittomaeki, K, Pelttari, LM, Ehrencrona, H, Borg, A, Kvist, A, Rivera, B, Hansen, TVO, Djursby, M, Lee, A, Dennis, J, Bowtell, DD, Traficante, N, Diez, O, Balmana, J, Gruber, SB, Chenevix-Trench, G, Jensen, A, Kjaer, SK, Hogdall, E, Castera, L, Garber, J, Janavicius, R, Osorio, A, Golmard, L, Vega, A, Couch, FJ, Robson, M, Gronwald, J, Domchek, SM, Culver, JO, de la Hoya, M, Easton, DF, Foulkes, WD, Tischkowitz, M, Meindl, A, Schmutzler, RK, Pharoah, PDP, Antoniou, AC, Yang, X, Song, H, Leslie, G, Engel, C, Hahnen, E, Auber, B, Horvath, J, Kast, K, Niederacher, D, Turnbull, C, Houlston, R, Hanson, H, Loveday, C, Dolinsky, JS, LaDuca, H, Ramus, SJ, Menon, U, Rosenthal, AN, Jacobs, I, Gayther, SA, Dicks, E, Nevanlinna, H, Aittomaeki, K, Pelttari, LM, Ehrencrona, H, Borg, A, Kvist, A, Rivera, B, Hansen, TVO, Djursby, M, Lee, A, Dennis, J, Bowtell, DD, Traficante, N, Diez, O, Balmana, J, Gruber, SB, Chenevix-Trench, G, Jensen, A, Kjaer, SK, Hogdall, E, Castera, L, Garber, J, Janavicius, R, Osorio, A, Golmard, L, Vega, A, Couch, FJ, Robson, M, Gronwald, J, Domchek, SM, Culver, JO, de la Hoya, M, Easton, DF, Foulkes, WD, Tischkowitz, M, Meindl, A, Schmutzler, RK, Pharoah, PDP, and Antoniou, AC
Abstract: BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
Published: 2020

20. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Author: Martins, FC, Couturier, D-L, Paterson, A, Karnezis, AN, Christine, C, Nazeran, TM, Odunsi, A, Gentry-Maharaj, A, Vrvilo, A, Hein, A, Talhouk, A, Osorio, A, Hartkopf, AD, Brooks-Wilson, A, DeFazio, A, Fischer, A, Hartmann, A, Hernandez, BY, McCauley, BM, Karpinskyj, C, de Sousa, CB, Hogdall, C, Tiezzi, DG, Herpel, E, Taran, FA, Modugno, F, Keeney, G, Nelson, G, Steed, H, Song, H, Luk, H, Benitez, J, Alsop, J, Koziak, JM, Lester, J, Rothstein, JH, de Andrade, JM, Lundvall, L, Paz-Ares, L, Robles-Diaz, L, Wilkens, LR, Garcia, MJ, Intermaggio, MP, Alcaraz, M-L, Brett, MA, Beckmann, MW, Jimenez-Linan, M, Anglesio, M, Carney, ME, Schneider, M, Traficante, N, Pejovic, N, Singh, N, Le, N, Sinn, P, Ghatage, P, Erber, R, Edwards, R, Vierkant, R, Ness, RB, Leung, S, Orsulic, S, Brucker, SY, Kaufmann, SH, Fereday, S, Gayther, S, Winham, SJ, Kommoss, S, Pejovic, T, Longacre, TA, McGuire, V, Rhenius, V, Sieh, W, Shvetsov, YB, Whittemore, AS, Staebler, A, Karlan, BY, Rodriguez-Antona, C, Bowtell, DD, Goode, EL, Hogdall, E, Candido dos Reis, FJ, Gronwald, J, Chang-Claude, J, Moysich, KB, Kelemen, LE, Cook, LS, Goodman, MT, Fasching, PA, Crawford, R, Deen, S, Menon, U, Huntsman, DG, Kobel, M, Ramus, SJ, Pharoah, PDP, Brenton, JD, Martins, FC, Couturier, D-L, Paterson, A, Karnezis, AN, Christine, C, Nazeran, TM, Odunsi, A, Gentry-Maharaj, A, Vrvilo, A, Hein, A, Talhouk, A, Osorio, A, Hartkopf, AD, Brooks-Wilson, A, DeFazio, A, Fischer, A, Hartmann, A, Hernandez, BY, McCauley, BM, Karpinskyj, C, de Sousa, CB, Hogdall, C, Tiezzi, DG, Herpel, E, Taran, FA, Modugno, F, Keeney, G, Nelson, G, Steed, H, Song, H, Luk, H, Benitez, J, Alsop, J, Koziak, JM, Lester, J, Rothstein, JH, de Andrade, JM, Lundvall, L, Paz-Ares, L, Robles-Diaz, L, Wilkens, LR, Garcia, MJ, Intermaggio, MP, Alcaraz, M-L, Brett, MA, Beckmann, MW, Jimenez-Linan, M, Anglesio, M, Carney, ME, Schneider, M, Traficante, N, Pejovic, N, Singh, N, Le, N, Sinn, P, Ghatage, P, Erber, R, Edwards, R, Vierkant, R, Ness, RB, Leung, S, Orsulic, S, Brucker, SY, Kaufmann, SH, Fereday, S, Gayther, S, Winham, SJ, Kommoss, S, Pejovic, T, Longacre, TA, McGuire, V, Rhenius, V, Sieh, W, Shvetsov, YB, Whittemore, AS, Staebler, A, Karlan, BY, Rodriguez-Antona, C, Bowtell, DD, Goode, EL, Hogdall, E, Candido dos Reis, FJ, Gronwald, J, Chang-Claude, J, Moysich, KB, Kelemen, LE, Cook, LS, Goodman, MT, Fasching, PA, Crawford, R, Deen, S, Menon, U, Huntsman, DG, Kobel, M, Ramus, SJ, Pharoah, PDP, and Brenton, JD
Abstract: BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Published: 2020

21. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author: Jiang, X., Finucane, H.K., Schumacher, F.R., Schmit, S.L., Tyrer, J.P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K.B., Dennis, J., Conti, D.V., Casey, G., Gaudet, M.M., Huyghe, J.R., Albanes, D., Aldrich, M.C., Andrew, A.S., Andrulis, I.L., Anton-Culver, H., Antoniou, A.C., Antonenkova, N.N., Arnold, S.M., Aronson, K.J., Arun, B.K., Bandera, E.V., Barkardottir, R.B., Barnes, D.R., Batra, J., Beckmann, M.W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S.I., Bickeboller, H., Bien, S.A., Blomqvist, C., Boccia, S., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Brauch, H., Brenner, H., Brenton, J.D., Brook, M.N., Brunet, J., Brunnstrom, H., Buchanan, D.D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M.A., Campbell, I., Campbell, P.T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A.L., Chan, A.T., Chang-Claude, J., Chanock, S.J., Chen, C., Christiani, D.C., Claes, K.B.M., Claessens, F., Clements, J., Collee, J.M., Correa, M.C., Couch, F.J., Cox, A., Cunningham, J.M., Cybulski, C., Czene, K., Daly, M.B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J.L., Dork, T., Duell, E.J., Dunning, A.M., Dwek, M., Eccles, D.M., Edlund, C.K., Edwards, D.R.V., Ellberg, C., Evans, D.G., Fasching, P.A., Ferris, R.L., Liloglou, T., Figueiredo, J.C., Fletcher, O., Fortner, R.T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S.J., Ganz, P.A., Garber, J., Garcia-Saenz, J.A., Gayther, S.A., Giles, G.G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Goode, E.L., Goodman, M.T., Goodman, G., Grankvist, K., Greene, M.H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F.C., Hamilton, R.J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y.C., Hopper, J.L., Houlston, R., Hulick, P.J., Hunter, D.J., Huntsman, D.G., Idos, G., Imyanitov, E.N., Ingles, S.A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M.A., Johansson, M., John, E.M., Joshi, A.D., Kaneva, R., Karlan, B.Y., Kelemen, L.E., Kuhl, T., Khaw, K.T., Khusnutdinova, E., Kibel, A.S., Kiemeney, L.A., Kim, J., Kjaer, S.K., Knight, J.A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V.N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M.T., Lazarus, P., N.D. le, Lee, E., Lejbkowicz, F., Lenz, H.J., Leslie, G., Lessel, D., Lester, J., Levine, D.A., Li, L., Li, C.I., Lindblom, A., Lindor, N.M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R.L., MacInnis, R.J., Modugno, F., Montagna, M., Moreno, V., Moysich, K.B., Mucci, L., Muir, K., Mulligan, A.M., Nathanson, K.L., Neal, D.E., Ness, A.R., Neuhausen, S.L., Nevanlinna, H., Newcomb, P.A., Newcomb, L.F., Nielsen, F.C., Nikitina-Zake, L., Nordestgaard, B.G., Nussbaum, R.L., Offit, K., Olah, E., Olama, A.A. al, Olopade, O.I., Olshan, A.F., Olsson, H., Osorio, A., Pandha, H., Park, J.Y., Pashayan, N., Parsons, M.T., Pejovic, T., Penney, K.L., Peters, W.H.M., Phelan, C.M., Phipps, A.I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S.J., Raskin, L., Rennert, G., Rennert, H.S., Rensburg, E.J., Riggan, M.J., Risch, H.A., Risch, A., Roobol, M.J., Rosenstein, B.S., Rossing, M.A., Ruyck, K., Saloustros, E., Sandler, D.P., Sawyer, E.J., Schabath, M.B., Schleutker, J., Schmidt, M.K., Setiawan, V.W., Shen, H.B., Siegel, E.M., Sieh, W., Singer, C.F., Slattery, M.L., Sorensen, K.D., Southey, M.C., Spurdle, A.B., Stanford, J.L., Stevens, V.L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A.J., Tajara, E.H., Tangen, C.M., Tardon, A., Taylor, J.A., Teare, M.D., Teixeira, M.R., Terry, M.B., Terry, K.L., Thibodeau, S.N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A.E., Torres, D., Townsend, P.A., Travis, R.C., Tung, N., and Tworoger
Published: 2019

22. Shared heritability and functional enrichment across six solid cancers.

Author: Fletcher O., Tardon A., Taylor J.A., Teare M.D., Teixeira M.R., Terry M.B., Terry K.L., Thibodeau S.N., Thomassen M., Bjorge L., Tischkowitz M., Toland A.E., Torres D., Townsend P.A., Travis R.C., Tung N., Tworoger S.S., Ulrich C.M., Usmani N., Vachon C.M., Van Nieuwenhuysen E., Vega A., Aguado-Barrera M.E., Wang Q., Webb P.M., Weinberg C.R., Weinstein S., Weissler M.C., Weitzel J.N., West C.M.L., White E., Whittemore A.S., Wichmann H.-E., Wiklund F., Winqvist R., Wolk A., Woll P., Woods M., Wu A.H., Wu X., Yannoukakos D., Zheng W., Zienolddiny S., Ziogas A., Zorn K.K., Lane J.M., Saxena R., Thomas D., Hung R.J., Diergaarde B., McKay J., Peters U., Hsu L., Garcia-Closas M., Eeles R.A., Chenevix-Trench G., Brennan P.J., Haiman C.A., Simard J., Easton D.F., Gruber S.B., Pharoah P.D.P., Price A.L., Pasaniuc B., Amos C.I., Kraft P., Lindstrom S., Chen C., Anton-Culver H., Antoniou A.C., Antonenkova N.N., Arnold S.M., Jiang X., Finucane H.K., Schumacher F.R., Schmit S.L., Tyrer J.P., Han Y., Michailidou K., Lesseur C., Kuchenbaecker K.B., Dennis J., Conti D.V., Casey G., Gaudet M.M., Huyghe J.R., Albanes D., Aldrich M.C., Andrew A.S., Andrulis I.L., Aronson K.J., Arun B.K., Bandera E.V., Barkardottir R.B., Barnes D.R., Batra J., Beckmann M.W., Benitez J., Benlloch S., Berchuck A., Berndt S.I., Bickeboller H., Bien S.A., Blomqvist C., Boccia S., Bogdanova N.V., Bojesen S.E., Bolla M.K., Brauch H., Brenner H., Brenton J.D., Brook M.N., Brunet J., Brunnstrom H., Buchanan D.D., Burwinkel B., Butzow R., Cadoni G., Caldes T., Caligo M.A., Campbell I., Campbell P.T., Cancel-Tassin G., Cannon-Albright L., Campa D., Caporaso N., Carvalho A.L., Chan A.T., Chang-Claude J., Chanock S.J., Christiani D.C., Claes K.B.M., Claessens F., Clements J., Collee J.M., Correa M.C., Couch F.J., Cox A., Cunningham J.M., Cybulski C., Czene K., Daly M.B., deFazio A., Devilee P., Diez O., Gago-Dominguez M., Donovan J.L., Dork T., Duell E.J., Dunning A.M., Dwek M., Eccles D.M., Edlund C.K., Edwards D.R.V., Ellberg C., Evans D.G., Fasching P.A., Ferris R.L., Liloglou T., Figueiredo J.C., Fortner R.T., Fostira F., Franceschi S., Friedman E., Gallinger S.J., Ganz P.A., Garber J., Garcia-Saenz J.A., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Goode E.L., Goodman M.T., Goodman G., Grankvist K., Greene M.H., Gronberg H., Gronwald J., Guenel P., Hakansson N., Hall P., Hamann U., Hamdy F.C., Hamilton R.J., Hampe J., Haugen A., Heitz F., Herrero R., Hillemanns P., Hoffmeister M., Hogdall E., Hong Y.-C., Hopper J.L., Houlston R., Hulick P.J., Hunter D.J., Huntsman D.G., Idos G., Imyanitov E.N., Ingles S.A., Isaacs C., Jakubowska A., James P., Jenkins M.A., Johansson M., John E.M., Joshi A.D., Kaneva R., Karlan B.Y., Kelemen L.E., Kuhl T., Khaw K.-T., Khusnutdinova E., Kibel A.S., Kiemeney L.A., Kim J., Kjaer S.K., Knight J.A., Kogevinas M., Kote-Jarai Z., Koutros S., Kristensen V.N., Kupryjanczyk J., Lacko M., Lam S., Lambrechts D., Landi M.T., Lazarus P., Le N.D., Lee E., Lejbkowicz F., Lenz H.-J., Leslie G., Lessel D., Lester J., Levine D.A., Li L., Li C.I., Lindblom A., Lindor N.M., Liu G., Loupakis F., Lubinski J., Maehle L., Maier C., Mannermaa A., Marchand L.L., Margolin S., May T., McGuffog L., Meindl A., Middha P., Miller A., Milne R.L., MacInnis R.J., Modugno F., Montagna M., Moreno V., Moysich K.B., Mucci L., Muir K., Mulligan A.M., Nathanson K.L., Neal D.E., Ness A.R., Neuhausen S.L., Nevanlinna H., Newcomb P.A., Newcomb L.F., Nielsen F.C., Nikitina-Zake L., Nordestgaard B.G., Nussbaum R.L., Offit K., Olah E., Olama A.A.A., Olopade O.I., Olshan A.F., Olsson H., Osorio A., Pandha H., Park J.Y., Pashayan N., Parsons M.T., Pejovic T., Penney K.L., Peters W.H.M., Phelan C.M., Phipps A.I., Plaseska-Karanfilska D., Pring M., Prokofyeva D., Radice P., Stefansson K., Ramus S.J., Raskin L., Rennert G., Rennert H.S., van Rensburg E.J., Riggan M.J., Risch H.A., Risch A., Roobol M.J., Rosenstein B.S., Rossing M.A., De Ruyck K., Saloustros E., Sandler D.P., Sawyer E.J., Schabath M.B., Schleutker J., Schmidt M.K., Setiawan V.W., Shen H., Siegel E.M., Sieh W., Singer C.F., Slattery M.L., Sorensen K.D., Southey M.C., Spurdle A.B., Stanford J.L., Stevens V.L., Stintzing S., Stone J., Sundfeldt K., Sutphen R., Swerdlow A.J., Tajara E.H., Tangen C.M., Fletcher O., Tardon A., Taylor J.A., Teare M.D., Teixeira M.R., Terry M.B., Terry K.L., Thibodeau S.N., Thomassen M., Bjorge L., Tischkowitz M., Toland A.E., Torres D., Townsend P.A., Travis R.C., Tung N., Tworoger S.S., Ulrich C.M., Usmani N., Vachon C.M., Van Nieuwenhuysen E., Vega A., Aguado-Barrera M.E., Wang Q., Webb P.M., Weinberg C.R., Weinstein S., Weissler M.C., Weitzel J.N., West C.M.L., White E., Whittemore A.S., Wichmann H.-E., Wiklund F., Winqvist R., Wolk A., Woll P., Woods M., Wu A.H., Wu X., Yannoukakos D., Zheng W., Zienolddiny S., Ziogas A., Zorn K.K., Lane J.M., Saxena R., Thomas D., Hung R.J., Diergaarde B., McKay J., Peters U., Hsu L., Garcia-Closas M., Eeles R.A., Chenevix-Trench G., Brennan P.J., Haiman C.A., Simard J., Easton D.F., Gruber S.B., Pharoah P.D.P., Price A.L., Pasaniuc B., Amos C.I., Kraft P., Lindstrom S., Chen C., Anton-Culver H., Antoniou A.C., Antonenkova N.N., Arnold S.M., Jiang X., Finucane H.K., Schumacher F.R., Schmit S.L., Tyrer J.P., Han Y., Michailidou K., Lesseur C., Kuchenbaecker K.B., Dennis J., Conti D.V., Casey G., Gaudet M.M., Huyghe J.R., Albanes D., Aldrich M.C., Andrew A.S., Andrulis I.L., Aronson K.J., Arun B.K., Bandera E.V., Barkardottir R.B., Barnes D.R., Batra J., Beckmann M.W., Benitez J., Benlloch S., Berchuck A., Berndt S.I., Bickeboller H., Bien S.A., Blomqvist C., Boccia S., Bogdanova N.V., Bojesen S.E., Bolla M.K., Brauch H., Brenner H., Brenton J.D., Brook M.N., Brunet J., Brunnstrom H., Buchanan D.D., Burwinkel B., Butzow R., Cadoni G., Caldes T., Caligo M.A., Campbell I., Campbell P.T., Cancel-Tassin G., Cannon-Albright L., Campa D., Caporaso N., Carvalho A.L., Chan A.T., Chang-Claude J., Chanock S.J., Christiani D.C., Claes K.B.M., Claessens F., Clements J., Collee J.M., Correa M.C., Couch F.J., Cox A., Cunningham J.M., Cybulski C., Czene K., Daly M.B., deFazio A., Devilee P., Diez O., Gago-Dominguez M., Donovan J.L., Dork T., Duell E.J., Dunning A.M., Dwek M., Eccles D.M., Edlund C.K., Edwards D.R.V., Ellberg C., Evans D.G., Fasching P.A., Ferris R.L., Liloglou T., Figueiredo J.C., Fortner R.T., Fostira F., Franceschi S., Friedman E., Gallinger S.J., Ganz P.A., Garber J., Garcia-Saenz J.A., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Goode E.L., Goodman M.T., Goodman G., Grankvist K., Greene M.H., Gronberg H., Gronwald J., Guenel P., Hakansson N., Hall P., Hamann U., Hamdy F.C., Hamilton R.J., Hampe J., Haugen A., Heitz F., Herrero R., Hillemanns P., Hoffmeister M., Hogdall E., Hong Y.-C., Hopper J.L., Houlston R., Hulick P.J., Hunter D.J., Huntsman D.G., Idos G., Imyanitov E.N., Ingles S.A., Isaacs C., Jakubowska A., James P., Jenkins M.A., Johansson M., John E.M., Joshi A.D., Kaneva R., Karlan B.Y., Kelemen L.E., Kuhl T., Khaw K.-T., Khusnutdinova E., Kibel A.S., Kiemeney L.A., Kim J., Kjaer S.K., Knight J.A., Kogevinas M., Kote-Jarai Z., Koutros S., Kristensen V.N., Kupryjanczyk J., Lacko M., Lam S., Lambrechts D., Landi M.T., Lazarus P., Le N.D., Lee E., Lejbkowicz F., Lenz H.-J., Leslie G., Lessel D., Lester J., Levine D.A., Li L., Li C.I., Lindblom A., Lindor N.M., Liu G., Loupakis F., Lubinski J., Maehle L., Maier C., Mannermaa A., Marchand L.L., Margolin S., May T., McGuffog L., Meindl A., Middha P., Miller A., Milne R.L., MacInnis R.J., Modugno F., Montagna M., Moreno V., Moysich K.B., Mucci L., Muir K., Mulligan A.M., Nathanson K.L., Neal D.E., Ness A.R., Neuhausen S.L., Nevanlinna H., Newcomb P.A., Newcomb L.F., Nielsen F.C., Nikitina-Zake L., Nordestgaard B.G., Nussbaum R.L., Offit K., Olah E., Olama A.A.A., Olopade O.I., Olshan A.F., Olsson H., Osorio A., Pandha H., Park J.Y., Pashayan N., Parsons M.T., Pejovic T., Penney K.L., Peters W.H.M., Phelan C.M., Phipps A.I., Plaseska-Karanfilska D., Pring M., Prokofyeva D., Radice P., Stefansson K., Ramus S.J., Raskin L., Rennert G., Rennert H.S., van Rensburg E.J., Riggan M.J., Risch H.A., Risch A., Roobol M.J., Rosenstein B.S., Rossing M.A., De Ruyck K., Saloustros E., Sandler D.P., Sawyer E.J., Schabath M.B., Schleutker J., Schmidt M.K., Setiawan V.W., Shen H., Siegel E.M., Sieh W., Singer C.F., Slattery M.L., Sorensen K.D., Southey M.C., Spurdle A.B., Stanford J.L., Stevens V.L., Stintzing S., Stone J., Sundfeldt K., Sutphen R., Swerdlow A.J., Tajara E.H., and Tangen C.M.
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 x 10-8), breast and ovarian cancer (rg = 0.24, p = 7 x 10-5), breast and lung cancer (rg = 0.18, p =1.5 x 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 x 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Copyright © 2019, The Author(s).
Published: 2019

23. Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature Communications, (2019), 10, 1, (431), 10.1038/s41467-018-08054-4).

Author: Tangen C.M., Wu X., Yannoukakos D., Zheng W., Zienolddiny S., Ziogas A., Zorn K.K., Lane J.M., Saxena R., Thomas D., Hung R.J., Diergaarde B., McKay J., Peters U., Hsu L., Garcia-Closas M., Eeles R.A., Chenevix-Trench G., Brennan P.J., Haiman C.A., Simard J., Easton D.F., Gruber S.B., Pharoah P.D.P., Price A.L., Pasaniuc B., Amos C.I., Kraft P., Lindstrom S., Chen C., Jiang X., Finucane H.K., Schumacher F.R., Schmit S.L., Tyrer J.P., Han Y., Michailidou K., Lesseur C., Kuchenbaecker K.B., Dennis J., Conti D.V., Casey G., Gaudet M.M., Huyghe J.R., Albanes D., Aldrich M.C., Andrew A.S., Andrulis I.L., Anton-Culver H., Antoniou A.C., Antonenkova N.N., Arnold S.M., Aronson K.J., Arun B.K., Bandera E.V., Barkardottir R.B., Barnes D.R., Batra J., Beckmann M.W., Benitez J., Benlloch S., Berchuck A., Berndt S.I., Bickeboller H., Bien S.A., Blomqvist C., Boccia S., Bogdanova N.V., Bojesen S.E., Bolla M.K., Brauch H., Brenner H., Brenton J.D., Brook M.N., Brunet J., Brunnstrom H., Buchanan D.D., Burwinkel B., Butzow R., Cadoni G., Caldes T., Caligo M.A., Campbell I., Campbell P.T., Cancel-Tassin G., Cannon-Albright L., Campa D., Caporaso N., Carvalho A.L., Chan A.T., Chang-Claude J., Chanock S.J., Christiani D.C., Claes K.B.M., Claessens F., Clements J., Collee J.M., Correa M.C., Couch F.J., Cox A., Cunningham J.M., Cybulski C., Czene K., Daly M.B., deFazio A., Devilee P., Diez O., Gago-Dominguez M., Donovan J.L., Dork T., Duell E.J., Dunning A.M., Dwek M., Eccles D.M., Edlund C.K., Edwards D.R.V., Ellberg C., Evans D.G., Fasching P.A., Ferris R.L., Liloglou T., Figueiredo J.C., Fletcher O., Fortner R.T., Fostira F., Franceschi S., Friedman E., Gallinger S.J., Ganz P.A., Garber J., Garcia-Saenz J.A., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Goode E.L., Goodman M.T., Goodman G., Grankvist K., Greene M.H., Gronberg H., Gronwald J., Guenel P., Hakansson N., Hall P., Hamann U., Hamdy F.C., Hamilton R.J., Hampe J., Haugen A., Heitz F., Herrero R., Hillemanns P., Hoffmeister M., Hogdall E., Hong Y.-C., Hopper J.L., Houlston R., Hulick P.J., Hunter D.J., Huntsman D.G., Idos G., Imyanitov E.N., Ingles S.A., Isaacs C., Jakubowska A., James P., Jenkins M.A., Johansson M., John E.M., Joshi A.D., Kaneva R., Karlan B.Y., Kelemen L.E., Kuhl T., Khaw K.-T., Khusnutdinova E., Kibel A.S., Kiemeney L.A., Kim J., Kjaer S.K., Knight J.A., Kogevinas M., Kote-Jarai Z., Koutros S., Kristensen V.N., Kupryjanczyk J., Lacko M., Lam S., Lambrechts D., Landi M.T., Lazarus P., Le N.D., Lee E., Lejbkowicz F., Lenz H.-J., Leslie G., Lessel D., Lester J., Levine D.A., Li L., Li C.I., Lindblom A., Lindor N.M., Liu G., Loupakis F., Lubinski J., Maehle L., Maier C., Mannermaa A., Marchand L.L., Margolin S., May T., McGuffog L., Meindl A., Middha P., Miller A., Milne R.L., MacInnis R.J., Modugno F., Montagna M., Moreno V., Moysich K.B., Mucci L., Muir K., Mulligan A.M., Nathanson K.L., Neal D.E., Ness A.R., Neuhausen S.L., Nevanlinna H., Newcomb P.A., Newcomb L.F., Nielsen F.C., Nikitina-Zake L., Nordestgaard B.G., Nussbaum R.L., Offit K., Olah E., Olama A.A.A., Olopade O.I., Olshan A.F., Olsson H., Osorio A., Pandha H., Park J.Y., Pashayan N., Parsons M.T., Pejovic T., Penney K.L., Peters W.H.M., Phelan C.M., Phipps A.I., Plaseska-Karanfilska D., Pring M., Prokofyeva D., Radice P., Stefansson K., Ramus S.J., Raskin L., Rennert G., Rennert H.S., van Rensburg E.J., Riggan M.J., Risch H.A., Risch A., Roobol M.J., Rosenstein B.S., Rossing M.A., De Ruyck K., Saloustros E., Sandler D.P., Sawyer E.J., Schabath M.B., Schleutker J., Schmidt M.K., Setiawan V.W., Shen H., Siegel E.M., Sieh W., Singer C.F., Slattery M.L., Sorensen K.D., Southey M.C., Spurdle A.B., Stanford J.L., Stevens V.L., Stintzing S., Stone J., Sundfeldt K., Sutphen R., Swerdlow A.J., Tajara E.H., Tardon A., Taylor J.A., Teare M.D., Teixeira M.R., Terry M.B., Terry K.L., Thibodeau S.N., Thomassen M., Bjorge L., Tischkowitz M., Toland A.E., Torres D., Townsend P.A., Travis R.C., Tung N., Tworoger S.S., Ulrich C.M., Usmani N., Vachon C.M., Van Nieuwenhuysen E., Vega A., Aguado-Barrera M.E., Wang Q., Webb P.M., Weinberg C.R., Weinstein S., Weissler M.C., Weitzel J.N., West C.M.L., White E., Whittemore A.S., Wichmann H.-E., Wiklund F., Winqvist R., Wolk A., Woll P., Woods M., Wu A.H., Tangen C.M., Wu X., Yannoukakos D., Zheng W., Zienolddiny S., Ziogas A., Zorn K.K., Lane J.M., Saxena R., Thomas D., Hung R.J., Diergaarde B., McKay J., Peters U., Hsu L., Garcia-Closas M., Eeles R.A., Chenevix-Trench G., Brennan P.J., Haiman C.A., Simard J., Easton D.F., Gruber S.B., Pharoah P.D.P., Price A.L., Pasaniuc B., Amos C.I., Kraft P., Lindstrom S., Chen C., Jiang X., Finucane H.K., Schumacher F.R., Schmit S.L., Tyrer J.P., Han Y., Michailidou K., Lesseur C., Kuchenbaecker K.B., Dennis J., Conti D.V., Casey G., Gaudet M.M., Huyghe J.R., Albanes D., Aldrich M.C., Andrew A.S., Andrulis I.L., Anton-Culver H., Antoniou A.C., Antonenkova N.N., Arnold S.M., Aronson K.J., Arun B.K., Bandera E.V., Barkardottir R.B., Barnes D.R., Batra J., Beckmann M.W., Benitez J., Benlloch S., Berchuck A., Berndt S.I., Bickeboller H., Bien S.A., Blomqvist C., Boccia S., Bogdanova N.V., Bojesen S.E., Bolla M.K., Brauch H., Brenner H., Brenton J.D., Brook M.N., Brunet J., Brunnstrom H., Buchanan D.D., Burwinkel B., Butzow R., Cadoni G., Caldes T., Caligo M.A., Campbell I., Campbell P.T., Cancel-Tassin G., Cannon-Albright L., Campa D., Caporaso N., Carvalho A.L., Chan A.T., Chang-Claude J., Chanock S.J., Christiani D.C., Claes K.B.M., Claessens F., Clements J., Collee J.M., Correa M.C., Couch F.J., Cox A., Cunningham J.M., Cybulski C., Czene K., Daly M.B., deFazio A., Devilee P., Diez O., Gago-Dominguez M., Donovan J.L., Dork T., Duell E.J., Dunning A.M., Dwek M., Eccles D.M., Edlund C.K., Edwards D.R.V., Ellberg C., Evans D.G., Fasching P.A., Ferris R.L., Liloglou T., Figueiredo J.C., Fletcher O., Fortner R.T., Fostira F., Franceschi S., Friedman E., Gallinger S.J., Ganz P.A., Garber J., Garcia-Saenz J.A., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Goode E.L., Goodman M.T., Goodman G., Grankvist K., Greene M.H., Gronberg H., Gronwald J., Guenel P., Hakansson N., Hall P., Hamann U., Hamdy F.C., Hamilton R.J., Hampe J., Haugen A., Heitz F., Herrero R., Hillemanns P., Hoffmeister M., Hogdall E., Hong Y.-C., Hopper J.L., Houlston R., Hulick P.J., Hunter D.J., Huntsman D.G., Idos G., Imyanitov E.N., Ingles S.A., Isaacs C., Jakubowska A., James P., Jenkins M.A., Johansson M., John E.M., Joshi A.D., Kaneva R., Karlan B.Y., Kelemen L.E., Kuhl T., Khaw K.-T., Khusnutdinova E., Kibel A.S., Kiemeney L.A., Kim J., Kjaer S.K., Knight J.A., Kogevinas M., Kote-Jarai Z., Koutros S., Kristensen V.N., Kupryjanczyk J., Lacko M., Lam S., Lambrechts D., Landi M.T., Lazarus P., Le N.D., Lee E., Lejbkowicz F., Lenz H.-J., Leslie G., Lessel D., Lester J., Levine D.A., Li L., Li C.I., Lindblom A., Lindor N.M., Liu G., Loupakis F., Lubinski J., Maehle L., Maier C., Mannermaa A., Marchand L.L., Margolin S., May T., McGuffog L., Meindl A., Middha P., Miller A., Milne R.L., MacInnis R.J., Modugno F., Montagna M., Moreno V., Moysich K.B., Mucci L., Muir K., Mulligan A.M., Nathanson K.L., Neal D.E., Ness A.R., Neuhausen S.L., Nevanlinna H., Newcomb P.A., Newcomb L.F., Nielsen F.C., Nikitina-Zake L., Nordestgaard B.G., Nussbaum R.L., Offit K., Olah E., Olama A.A.A., Olopade O.I., Olshan A.F., Olsson H., Osorio A., Pandha H., Park J.Y., Pashayan N., Parsons M.T., Pejovic T., Penney K.L., Peters W.H.M., Phelan C.M., Phipps A.I., Plaseska-Karanfilska D., Pring M., Prokofyeva D., Radice P., Stefansson K., Ramus S.J., Raskin L., Rennert G., Rennert H.S., van Rensburg E.J., Riggan M.J., Risch H.A., Risch A., Roobol M.J., Rosenstein B.S., Rossing M.A., De Ruyck K., Saloustros E., Sandler D.P., Sawyer E.J., Schabath M.B., Schleutker J., Schmidt M.K., Setiawan V.W., Shen H., Siegel E.M., Sieh W., Singer C.F., Slattery M.L., Sorensen K.D., Southey M.C., Spurdle A.B., Stanford J.L., Stevens V.L., Stintzing S., Stone J., Sundfeldt K., Sutphen R., Swerdlow A.J., Tajara E.H., Tardon A., Taylor J.A., Teare M.D., Teixeira M.R., Terry M.B., Terry K.L., Thibodeau S.N., Thomassen M., Bjorge L., Tischkowitz M., Toland A.E., Torres D., Townsend P.A., Travis R.C., Tung N., Tworoger S.S., Ulrich C.M., Usmani N., Vachon C.M., Van Nieuwenhuysen E., Vega A., Aguado-Barrera M.E., Wang Q., Webb P.M., Weinberg C.R., Weinstein S., Weissler M.C., Weitzel J.N., West C.M.L., White E., Whittemore A.S., Wichmann H.-E., Wiklund F., Winqvist R., Wolk A., Woll P., Woods M., and Wu A.H.
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.Copyright © 2019, The Author(s).
Published: 2019

24. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

Author: Kjaer S.K., Bandera E.V., Cook L.S., Cramer D.W., Milne R.L., Winham S.J., Modugno F., Mukherjee B., Pearce C.L., Pharoah P.D.P., Pike M.C., Huntsman D., Hogdall E., Trabert B., Wentzensen N., Le N.D., Schildkraut J.M., Harris H.R., Chang-Claude J., Thompson P.J., Kim S., Wang M., Tyrer J.P., Jensen A., Wiensch A., Liu G., Lee A.W., Ness R.B., Salvatore M., Tworoger S.S., Whittemore A.S., Anton-Culver H., Sieh W., Olson S.H., Berchuck A., Goode E.L., Goodman M.T., Doherty J.A., Chenevix-Trench G., Rossing M.A., Webb P.M., Giles G.G., Terry K.L., Ziogas A., Fortner R.T., Menon U., Gayther S.A., Wu A.H., Song H., Brooks-Wilson A., Kjaer S.K., Bandera E.V., Cook L.S., Cramer D.W., Milne R.L., Winham S.J., Modugno F., Mukherjee B., Pearce C.L., Pharoah P.D.P., Pike M.C., Huntsman D., Hogdall E., Trabert B., Wentzensen N., Le N.D., Schildkraut J.M., Harris H.R., Chang-Claude J., Thompson P.J., Kim S., Wang M., Tyrer J.P., Jensen A., Wiensch A., Liu G., Lee A.W., Ness R.B., Salvatore M., Tworoger S.S., Whittemore A.S., Anton-Culver H., Sieh W., Olson S.H., Berchuck A., Goode E.L., Goodman M.T., Doherty J.A., Chenevix-Trench G., Rossing M.A., Webb P.M., Giles G.G., Terry K.L., Ziogas A., Fortner R.T., Menon U., Gayther S.A., Wu A.H., Song H., and Brooks-Wilson A.
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 x 10-4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.Copyright © 2018 UICC
Published: 2019

25. Shared heritability and functional enrichment across six solid cancers

Author: Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Published: 2019

26. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author: Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

27. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Author: Kim, S, Wang, M, Tyrer, JP, Jensen, A, Wiensch, A, Liu, G, Lee, AW, Ness, RB, Salvatore, M, Tworoger, SS, Whittemore, AS, Anton-Culver, H, Sieh, W, Olson, SH, Berchuck, A, Goode, EL, Goodman, MT, Doherty, JA, Chenevix-Trench, G, Rossing, MA, Webb, PM, Giles, GG, Terry, KL, Ziogas, A, Fortner, RT, Menon, U, Gayther, SA, Wu, AH, Song, H, Brooks-Wilson, A, Bandera, E, Cook, LS, Cramer, DW, Milne, RL, Winham, SJ, Kjaer, SK, Modugno, F, Thompson, PJ, Chang-Claude, J, Harris, HR, Schildkraut, JM, Le, ND, Wentzensen, N, Trabert, B, Hogdall, E, Huntsman, D, Pike, MC, Pharoah, PDP, Pearce, CL, Mukherjee, B, Kim, S, Wang, M, Tyrer, JP, Jensen, A, Wiensch, A, Liu, G, Lee, AW, Ness, RB, Salvatore, M, Tworoger, SS, Whittemore, AS, Anton-Culver, H, Sieh, W, Olson, SH, Berchuck, A, Goode, EL, Goodman, MT, Doherty, JA, Chenevix-Trench, G, Rossing, MA, Webb, PM, Giles, GG, Terry, KL, Ziogas, A, Fortner, RT, Menon, U, Gayther, SA, Wu, AH, Song, H, Brooks-Wilson, A, Bandera, E, Cook, LS, Cramer, DW, Milne, RL, Winham, SJ, Kjaer, SK, Modugno, F, Thompson, PJ, Chang-Claude, J, Harris, HR, Schildkraut, JM, Le, ND, Wentzensen, N, Trabert, B, Hogdall, E, Huntsman, D, Pike, MC, Pharoah, PDP, Pearce, CL, and Mukherjee, B
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.
Published: 2019

28. Shared heritability and functional enrichment across six solid cancers

Author: Jiang, X. (Xia), Finucane, H. K. (Hilary K.), Schumacher, F. R. (Fredrick R.), Schmit, S. L. (Stephanie L.), Tyrer, J. P. (Jonathan P.), Han, Y. (Younghun), Michailidou, K. (Kyriaki), Lesseur, C. (Corina), Kuchenbaecker, K. B. (Karoline B.), Dennis, J. (Joe), Conti, D. V. (David V.), Casey, G. (Graham), Gaudet, M. M. (Mia M.), Huyghe, J. R. (Jeroen R.), Albanes, D. (Demetrius), Aldrich, M. C. (Melinda C.), Andrew, A. S. (Angeline S.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A. C. (Antonis C.), Antonenkova, N. N. (Natalia N.), Arnold, S. M. (Susanne M.), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Bandera, E. V. (Elisa V.), Barkardottir, R. B. (Rosa B.), Barnes, D. R. (Daniel R.), Batra, J. (Jyotsna), Beckmann, M. W. (Matthias W.), Benitez, J. (Javier), Benlloch, S. (Sara), Berchuck, A. (Andrew), Berndt, S. I. (Sonja I.), Bickeboeller, H. (Heike), Bien, S. A. (Stephanie A.), Blomqvist, C. (Carl), Boccia, S. (Stefania), Bogdanova, N. V. (Natalia V.), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brenton, J. D. (James D.), Brook, M. N. (Mark N.), Brunet, J. (Joan), Brunnstrom, H. (Hans), Buchanan, D. D. (Daniel D.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Cadoni, G. (Gabriella), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campbell, I. (Ian), Campbell, P. T. (Peter T.), Cancel-Tassin, G. (Geraldine), Cannon-Albright, L. (Lisa), Campa, D. (Daniele), Caporaso, N. (Neil), Carvalho, A. L. (Andre L.), Chan, A. T. (Andrew T.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chen, C. (Chu), Christiani, D. C. (David C.), Claes, K. B. (Kathleen B. M.), Claessens, F. (Frank), Clements, J. (Judith), Collee, J. M. (J. Margriet), Correa, M. C. (Marcia Cruz), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cunningham, J. M. (Julie M.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M. B. (Mary B.), defazio, A. (Anna), Devilee, P. (Peter), Diez, O. (Orland), Gago-Dominguez, M. (Manuela), Donovan, J. L. (Jenny L.), Doerk, T. (Thilo), Duell, E. J. (Eric J.), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Edlund, C. K. (Christopher K.), Edwards, D. R. (Digna R. Velez), Ellberg, C. (Carolina), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Ferris, R. L. (Robert L.), Liloglou, T. (Triantafillos), Figueiredo, J. C. (Jane C.), Fletcher, O. (Olivia), Fortner, R. T. (Renee T.), Fostira, F. (Florentia), Franceschi, S. (Silvia), Friedman, E. (Eitan), Gallinger, S. J. (Steven J.), Ganz, P. A. (Patricia A.), Garber, J. (Judy), Garcia-Saenz, J. A. (Jose A.), Gayther, S. A. (Simon A.), Giles, G. G. (Graham G.), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Goode, E. L. (Ellen L.), Goodman, M. T. (Marc T.), Goodman, G. (Gary), Grankvist, K. (Kjell), Greene, M. H. (Mark H.), Gronberg, H. (Henrik), Gronwald, J. (Jacek), Guenel, P. (Pascal), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hamdy, F. C. (Freddie C.), Hamilton, R. J. (Robert J.), Hampe, J. (Jochen), Haugen, A. (Aage), Heitz, F. (Florian), Herrero, R. (Rolando), Hillemanns, P. (Peter), Hoffmeister, M. (Michael), Hogdall, E. (Estrid), Hong, Y.-C. (Yun-Chul), Hopper, J. L. (John L.), Houlston, R. (Richard), Hulick, P. J. (Peter J.), Hunter, D. J. (David J.), Huntsman, D. G. (David G.), Idos, G. (Gregory), Imyanitov, E. N. (Evgeny N.), Ingles, S. A. (Sue Ann), Isaacs, C. (Claudine), Jakubowska, A. (Anna), James, P. (Paul), Jenkins, M. A. (Mark A.), Johansson, M. (Mattias), Johansson, M. (Mikael), John, E. M. (Esther M.), Joshi, A. D. (Amit D.), Kaneva, R. (Radka), Karlan, B. Y. (Beth Y.), Kelemen, L. E. (Linda E.), Kuhl, T. (Tabea), Khaw, K.-T. (Kay-Tee), Khusnutdinova, E. (Elza), Kibel, A. S. (Adam S.), Kiemeney, L. A. (Lambertus A.), Kim, J. (Jeri), Kjaer, S. K. (Susanne K.), Knight, J. A. (Julia A.), Kogevinas, M. (Manolis), Kote-Jarai, Z. (Zsofia), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kupryjanczyk, J. (Jolanta), Lacko, M. (Martin), Lam, S. (Stephan), Lambrechts, D. (Diether), Landi, M. T. (Maria Teresa), Lazarus, P. (Philip), Le, N. D. (Nhu D.), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lenz, H.-J. (Heinz-Josef), Leslie, G. (Goska), Lessel, D. (Davor), Lester, J. (Jenny), Levine, D. A. (Douglas A.), Li, L. (Li), Li, C. I. (Christopher I.), Lindblom, A. (Annika), Lindor, N. M. (Noralane M.), Liu, G. (Geoffrey), Loupakis, F. (Fotios), Lubinski, J. (Jan), Maehle, L. (Lovise), Maier, C. (Christiane), Mannermaa, A. (Arto), Le Marchand, L. (Loic), Margolin, S. (Sara), May, T. (Taymaa), McGuffog, L. (Lesley), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, A. (Austin), Milne, R. L. (Roger L.), MacInnis, R. J. (Robert J.), Modugno, F. (Francesmary), Montagna, M. (Marco), Moreno, V. (Victor), Moysich, K. B. (Kirsten B.), Mucci, L. (Lorelei), Muir, K. (Kenneth), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neal, D. E. (David E.), Ness, A. R. (Andrew R.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Newcomb, P. A. (Polly A.), Newcomb, L. F. (Lisa F.), Nielsen, F. C. (Finn Cilius), Nikitina-Zake, L. (Liene), Nordestgaard, B. G. (Borge G.), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Al Olama, A. A. (Ali Amin), Olopade, O. I. (Olufunmilayo I.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Osorio, A. (Ana), Pandha, H. (Hardev), Park, J. Y. (Jong Y.), Pashayan, N. (Nora), Parsons, M. T. (Michael T.), Pejovic, T. (Tanja), Penney, K. L. (Kathryn L.), Peters, W. H. (Wilbert H. M.), Phelan, C. M. (Catherine M.), Phipps, A. I. (Amanda I.), Plaseska-Karanfilska, D. (Dijana), Pring, M. (Miranda), Prokofyeva, D. (Darya), Radice, P. (Paolo), Stefansson, K. (Kari), Ramus, S. J. (Susan J.), Raskin, L. (Leon), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), van Rensburg, E. J. (Elizabeth J.), Riggan, M. J. (Marjorie J.), Risch, H. A. (Harvey A.), Risch, A. (Angela), Roobol, M. J. (Monique J.), Rosenstein, B. S. (Barry S.), Rossing, M. A. (Mary Anne), De Ruyck, K. (Kim), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schabath, M. B. (Matthew B.), Schleutker, J. (Johanna), Schmidt, M. K. (Marjanka K.), Setiawan, V. W. (V. Wendy), Shen, H. (Hongbing), Siegel, E. M. (Erin M.), Sieh, W. (Weiva), Singer, C. F. (Christian F.), Slattery, M. L. (Martha L.), Sorensen, K. D. (Karina Dalsgaard), Southey, M. C. (Melissa C.), Spurdle, A. B. (Amanda B.), Stanford, J. L. (Janet L.), Stevens, V. L. (Victoria L.), Stintzing, S. (Sebastian), Stone, J. (Jennifer), Sundfeldt, K. (Karin), Sutphen, R. (Rebecca), Swerdlow, A. J. (Anthony J.), Tajara, E. H. (Eloiza H.), Tangen, C. M. (Catherine M.), Tardon, A. (Adonina), Taylor, J. A. (Jack A.), Teare, M. D. (M. Dawn), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Terry, K. L. (Kathryn L.), Thibodeau, S. N. (Stephen N.), Thomassen, M. (Mads), Bjorge, L. (Line), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Townsend, P. A. (Paul A.), Travis, R. C. (Ruth C.), Tung, N. (Nadine), Tworoger, S. S. (Shelley S.), Ulrich, C. M. (Cornelia M.), Usmani, N. (Nawaid), Vachon, C. M. (Celine M.), Van Nieuwenhuysen, E. (Els), Vega, A. (Ana), Aguado-Barrera, M. E. (Miguel Elias), Wang, Q. (Qin), Webb, P. M. (Penelope M.), Weinberg, C. R. (Clarice R.), Weinstein, S. (Stephanie), Weissler, M. C. (Mark C.), Weitzel, J. N. (Jeffrey N.), West, C. M. (Catharine M. L.), White, E. (Emily), Whittemore, A. S. (Alice S.), Wichmann, H.-E. (H-Erich), Wiklund, F. (Fredrik), Winqvist, R. (Robert), Wolk, A. (Alicja), Woll, P. (Penella), Woods, M. (Michael), Wu, A. H. (Anna H.), Wu, X. (Xifeng), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zienolddiny, S. (Shanbeh), Ziogas, A. (Argyrios), Zorn, K. K. (Kristin K.), Lane, J. M. (Jacqueline M.), Saxena, R. (Richa), Thomas, D. (Duncan), Hung, R. J. (Rayjean J.), Diergaarde, B. (Brenda), Mckay, J. (James), Peters, U. (Ulrike), Hsu, L. (Li), Garcia-Closas, M. (Montserrat), Eeles, R. A. (Rosalind A.), Chenevix-Trench, G. (Georgia), Brennan, P. J. (Paul J.), Haiman, C. A. (Christopher A.), Simard, J. (Jacques), Easton, D. F. (Douglas F.), Gruber, S. B. (Stephen B.), Pharoah, P. D. (Paul D. P.), Price, A. L. (Alkes L.), Pasaniuc, B. (Bogdan), Amos, C. I. (Christopher I.), Kraft, P. (Peter), Lindstrom, S. (Sara), Jiang, X. (Xia), Finucane, H. K. (Hilary K.), Schumacher, F. R. (Fredrick R.), Schmit, S. L. (Stephanie L.), Tyrer, J. P. (Jonathan P.), Han, Y. (Younghun), Michailidou, K. (Kyriaki), Lesseur, C. (Corina), Kuchenbaecker, K. B. (Karoline B.), Dennis, J. (Joe), Conti, D. V. (David V.), Casey, G. (Graham), Gaudet, M. M. (Mia M.), Huyghe, J. R. (Jeroen R.), Albanes, D. (Demetrius), Aldrich, M. C. (Melinda C.), Andrew, A. S. (Angeline S.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A. C. (Antonis C.), Antonenkova, N. N. (Natalia N.), Arnold, S. M. (Susanne M.), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Bandera, E. V. (Elisa V.), Barkardottir, R. B. (Rosa B.), Barnes, D. R. (Daniel R.), Batra, J. (Jyotsna), Beckmann, M. W. (Matthias W.), Benitez, J. (Javier), Benlloch, S. (Sara), Berchuck, A. (Andrew), Berndt, S. I. (Sonja I.), Bickeboeller, H. (Heike), Bien, S. A. (Stephanie A.), Blomqvist, C. (Carl), Boccia, S. (Stefania), Bogdanova, N. V. (Natalia V.), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brenton, J. D. (James D.), Brook, M. N. (Mark N.), Brunet, J. (Joan), Brunnstrom, H. (Hans), Buchanan, D. D. (Daniel D.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Cadoni, G. (Gabriella), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campbell, I. (Ian), Campbell, P. T. (Peter T.), Cancel-Tassin, G. (Geraldine), Cannon-Albright, L. (Lisa), Campa, D. (Daniele), Caporaso, N. (Neil), Carvalho, A. L. (Andre L.), Chan, A. T. (Andrew T.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chen, C. (Chu), Christiani, D. C. (David C.), Claes, K. B. (Kathleen B. M.), Claessens, F. (Frank), Clements, J. (Judith), Collee, J. M. (J. Margriet), Correa, M. C. (Marcia Cruz), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cunningham, J. M. (Julie M.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M. B. (Mary B.), defazio, A. (Anna), Devilee, P. (Peter), Diez, O. (Orland), Gago-Dominguez, M. (Manuela), Donovan, J. L. (Jenny L.), Doerk, T. (Thilo), Duell, E. J. (Eric J.), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Edlund, C. K. (Christopher K.), Edwards, D. R. (Digna R. Velez), Ellberg, C. (Carolina), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Ferris, R. L. (Robert L.), Liloglou, T. (Triantafillos), Figueiredo, J. C. (Jane C.), Fletcher, O. (Olivia), Fortner, R. T. (Renee T.), Fostira, F. (Florentia), Franceschi, S. (Silvia), Friedman, E. (Eitan), Gallinger, S. J. (Steven J.), Ganz, P. A. (Patricia A.), Garber, J. (Judy), Garcia-Saenz, J. A. (Jose A.), Gayther, S. A. (Simon A.), Giles, G. G. (Graham G.), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Goode, E. L. (Ellen L.), Goodman, M. T. (Marc T.), Goodman, G. (Gary), Grankvist, K. (Kjell), Greene, M. H. (Mark H.), Gronberg, H. (Henrik), Gronwald, J. (Jacek), Guenel, P. (Pascal), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hamdy, F. C. (Freddie C.), Hamilton, R. J. (Robert J.), Hampe, J. (Jochen), Haugen, A. (Aage), Heitz, F. (Florian), Herrero, R. (Rolando), Hillemanns, P. (Peter), Hoffmeister, M. (Michael), Hogdall, E. (Estrid), Hong, Y.-C. (Yun-Chul), Hopper, J. L. (John L.), Houlston, R. (Richard), Hulick, P. J. (Peter J.), Hunter, D. J. (David J.), Huntsman, D. G. (David G.), Idos, G. (Gregory), Imyanitov, E. N. (Evgeny N.), Ingles, S. A. (Sue Ann), Isaacs, C. (Claudine), Jakubowska, A. (Anna), James, P. (Paul), Jenkins, M. A. (Mark A.), Johansson, M. (Mattias), Johansson, M. (Mikael), John, E. M. (Esther M.), Joshi, A. D. (Amit D.), Kaneva, R. (Radka), Karlan, B. Y. (Beth Y.), Kelemen, L. E. (Linda E.), Kuhl, T. (Tabea), Khaw, K.-T. (Kay-Tee), Khusnutdinova, E. (Elza), Kibel, A. S. (Adam S.), Kiemeney, L. A. (Lambertus A.), Kim, J. (Jeri), Kjaer, S. K. (Susanne K.), Knight, J. A. (Julia A.), Kogevinas, M. (Manolis), Kote-Jarai, Z. (Zsofia), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kupryjanczyk, J. (Jolanta), Lacko, M. (Martin), Lam, S. (Stephan), Lambrechts, D. (Diether), Landi, M. T. (Maria Teresa), Lazarus, P. (Philip), Le, N. D. (Nhu D.), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lenz, H.-J. (Heinz-Josef), Leslie, G. (Goska), Lessel, D. (Davor), Lester, J. (Jenny), Levine, D. A. (Douglas A.), Li, L. (Li), Li, C. I. (Christopher I.), Lindblom, A. (Annika), Lindor, N. M. (Noralane M.), Liu, G. (Geoffrey), Loupakis, F. (Fotios), Lubinski, J. (Jan), Maehle, L. (Lovise), Maier, C. (Christiane), Mannermaa, A. (Arto), Le Marchand, L. (Loic), Margolin, S. (Sara), May, T. (Taymaa), McGuffog, L. (Lesley), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, A. (Austin), Milne, R. L. (Roger L.), MacInnis, R. J. (Robert J.), Modugno, F. (Francesmary), Montagna, M. (Marco), Moreno, V. (Victor), Moysich, K. B. (Kirsten B.), Mucci, L. (Lorelei), Muir, K. (Kenneth), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neal, D. E. (David E.), Ness, A. R. (Andrew R.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Newcomb, P. A. (Polly A.), Newcomb, L. F. (Lisa F.), Nielsen, F. C. (Finn Cilius), Nikitina-Zake, L. (Liene), Nordestgaard, B. G. (Borge G.), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Al Olama, A. A. (Ali Amin), Olopade, O. I. (Olufunmilayo I.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Osorio, A. (Ana), Pandha, H. (Hardev), Park, J. Y. (Jong Y.), Pashayan, N. (Nora), Parsons, M. T. (Michael T.), Pejovic, T. (Tanja), Penney, K. L. (Kathryn L.), Peters, W. H. (Wilbert H. M.), Phelan, C. M. (Catherine M.), Phipps, A. I. (Amanda I.), Plaseska-Karanfilska, D. (Dijana), Pring, M. (Miranda), Prokofyeva, D. (Darya), Radice, P. (Paolo), Stefansson, K. (Kari), Ramus, S. J. (Susan J.), Raskin, L. (Leon), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), van Rensburg, E. J. (Elizabeth J.), Riggan, M. J. (Marjorie J.), Risch, H. A. (Harvey A.), Risch, A. (Angela), Roobol, M. J. (Monique J.), Rosenstein, B. S. (Barry S.), Rossing, M. A. (Mary Anne), De Ruyck, K. (Kim), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schabath, M. B. (Matthew B.), Schleutker, J. (Johanna), Schmidt, M. K. (Marjanka K.), Setiawan, V. W. (V. Wendy), Shen, H. (Hongbing), Siegel, E. M. (Erin M.), Sieh, W. (Weiva), Singer, C. F. (Christian F.), Slattery, M. L. (Martha L.), Sorensen, K. D. (Karina Dalsgaard), Southey, M. C. (Melissa C.), Spurdle, A. B. (Amanda B.), Stanford, J. L. (Janet L.), Stevens, V. L. (Victoria L.), Stintzing, S. (Sebastian), Stone, J. (Jennifer), Sundfeldt, K. (Karin), Sutphen, R. (Rebecca), Swerdlow, A. J. (Anthony J.), Tajara, E. H. (Eloiza H.), Tangen, C. M. (Catherine M.), Tardon, A. (Adonina), Taylor, J. A. (Jack A.), Teare, M. D. (M. Dawn), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Terry, K. L. (Kathryn L.), Thibodeau, S. N. (Stephen N.), Thomassen, M. (Mads), Bjorge, L. (Line), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Townsend, P. A. (Paul A.), Travis, R. C. (Ruth C.), Tung, N. (Nadine), Tworoger, S. S. (Shelley S.), Ulrich, C. M. (Cornelia M.), Usmani, N. (Nawaid), Vachon, C. M. (Celine M.), Van Nieuwenhuysen, E. (Els), Vega, A. (Ana), Aguado-Barrera, M. E. (Miguel Elias), Wang, Q. (Qin), Webb, P. M. (Penelope M.), Weinberg, C. R. (Clarice R.), Weinstein, S. (Stephanie), Weissler, M. C. (Mark C.), Weitzel, J. N. (Jeffrey N.), West, C. M. (Catharine M. L.), White, E. (Emily), Whittemore, A. S. (Alice S.), Wichmann, H.-E. (H-Erich), Wiklund, F. (Fredrik), Winqvist, R. (Robert), Wolk, A. (Alicja), Woll, P. (Penella), Woods, M. (Michael), Wu, A. H. (Anna H.), Wu, X. (Xifeng), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zienolddiny, S. (Shanbeh), Ziogas, A. (Argyrios), Zorn, K. K. (Kristin K.), Lane, J. M. (Jacqueline M.), Saxena, R. (Richa), Thomas, D. (Duncan), Hung, R. J. (Rayjean J.), Diergaarde, B. (Brenda), Mckay, J. (James), Peters, U. (Ulrike), Hsu, L. (Li), Garcia-Closas, M. (Montserrat), Eeles, R. A. (Rosalind A.), Chenevix-Trench, G. (Georgia), Brennan, P. J. (Paul J.), Haiman, C. A. (Christopher A.), Simard, J. (Jacques), Easton, D. F. (Douglas F.), Gruber, S. B. (Stephen B.), Pharoah, P. D. (Paul D. P.), Price, A. L. (Alkes L.), Pasaniuc, B. (Bogdan), Amos, C. I. (Christopher I.), Kraft, P. (Peter), and Lindstrom, S. (Sara)
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Published: 2019

29. Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature Communications, (2019), 10, 1, (431), 10.1038/s41467-018-08054-4)

Author: Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeboller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnstrom, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, Chen, Christiani, D. C., Claes, K. B. M., Claessens, F., Clements, J., Collee, J. M., Correa, M. C., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Dork, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D. R. V., Ellberg, C., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., Garcia-Saenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y. -C., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S. A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kuhl, T., Khaw, K. -T., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M. T., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H. -J., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L. L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olama, A. A. A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. H. M., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V. W., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M. E., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. M. L., White, E., Whittemore, A. S., Wichmann, H. -E., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., McKay, J., Peters, U., Hsu, L., Garcia-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. D. P., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindstrom, S., Boccia S. (ORCID:0000-0002-1864-749X), Cadoni G. (ORCID:0000-0001-8244-784X), Chen C., Liu G., Wang Q., Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeboller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnstrom, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, Chen, Christiani, D. C., Claes, K. B. M., Claessens, F., Clements, J., Collee, J. M., Correa, M. C., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Dork, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D. R. V., Ellberg, C., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., Garcia-Saenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y. -C., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S. A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kuhl, T., Khaw, K. -T., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M. T., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H. -J., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L. L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olama, A. A. A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. H. M., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V. W., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M. E., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. M. L., White, E., Whittemore, A. S., Wichmann, H. -E., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., McKay, J., Peters, U., Hsu, L., Garcia-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. D. P., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindstrom, S., Boccia S. (ORCID:0000-0002-1864-749X), Cadoni G. (ORCID:0000-0001-8244-784X), Chen C., Liu G., and Wang Q.
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

30. The genetic landscape of 87 ovarian germ cell tumors

Author: Van Nieuwenhuysen, E. Busschaert, P. Neven, P. Han, S.N. Moerman, P. Liontos, M. Papaspirou, M. Kupryjanczyk, J. Hogdall, C. Hogdall, E. Oaknin, A. Garcia, A. Mahner, S. Trillsch, F. Cibula, D. Heitz, F. Concin, N. Speiser, P. Salvesen, H. Sehouli, J. Lambrechts, D. Vergote, I.
Abstract: Background: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. Methods: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. Results: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. Conclusion: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT. © 2018
Published: 2018

31. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Kelemen, L.E., Earp, M., Fridley, B.L., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Lambrechts, D., Lambrechts, S., Nieuwenhuysen, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Behrens, S., Moysich, K.B., Cannioto, R., Lele, S., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Thompson, P.J., Wilkens, L.R., Dork, T., Antonenkova, N., Bogdanova, N., Hillemanns, P., Runnebaum, I.B., Bois, A. du, Harter, P., Heitz, F., Schwaab, I., Butzow, R., Pelttari, L.M., Nevanlinna, H., Modugno, F., Edwards, R.P., Kelley, J.L., Ness, R.B., Karlan, B.Y., Lester, J., Orsulic, S., Walsh, C., Kjaer, S.K., Jensen, A., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Bruinsma, F., Southey, M.C., Hildebrandt, M.A., Liang, D., Lu, K., Wu, X., Sellers, T.A., Levine, D.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Bandera, E.V., Olson, S.H., Orlow, I., Thomsen, L.C., Bjorge, L., Krakstad, C., Tangen, I.L., Kiemeney, L.A.L.M., Aben, K.K.H., Massuger, L.F., Altena, A.M. van, Pejovic, T., Bean, Y., Kellar, M., Cook, L.S., Le, N.D., Brooks-Wilson, A., Gronwald, J., Cybulski, C., Jakubowska, A., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Hogdall, E., Engelholm, S.A., Hogdall, C., Lundvall, L., Nedergaard, L., Pharoah, P.D., Dicks, E., Song, H., Tyrer, J.P., McNeish, I., Siddiqui, N., Carty, K., Goode, E.L., Berchuck, A., Kelemen, L.E., Earp, M., Fridley, B.L., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Lambrechts, D., Lambrechts, S., Nieuwenhuysen, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Behrens, S., Moysich, K.B., Cannioto, R., Lele, S., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Thompson, P.J., Wilkens, L.R., Dork, T., Antonenkova, N., Bogdanova, N., Hillemanns, P., Runnebaum, I.B., Bois, A. du, Harter, P., Heitz, F., Schwaab, I., Butzow, R., Pelttari, L.M., Nevanlinna, H., Modugno, F., Edwards, R.P., Kelley, J.L., Ness, R.B., Karlan, B.Y., Lester, J., Orsulic, S., Walsh, C., Kjaer, S.K., Jensen, A., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Bruinsma, F., Southey, M.C., Hildebrandt, M.A., Liang, D., Lu, K., Wu, X., Sellers, T.A., Levine, D.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Bandera, E.V., Olson, S.H., Orlow, I., Thomsen, L.C., Bjorge, L., Krakstad, C., Tangen, I.L., Kiemeney, L.A.L.M., Aben, K.K.H., Massuger, L.F., Altena, A.M. van, Pejovic, T., Bean, Y., Kellar, M., Cook, L.S., Le, N.D., Brooks-Wilson, A., Gronwald, J., Cybulski, C., Jakubowska, A., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Hogdall, E., Engelholm, S.A., Hogdall, C., Lundvall, L., Nedergaard, L., Pharoah, P.D., Dicks, E., Song, H., Tyrer, J.P., McNeish, I., Siddiqui, N., Carty, K., Goode, E.L., and Berchuck, A.
Abstract: Contains fulltext : 195643.pdf (publisher's version ) (Open Access), Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97(-)1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03(-)1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

32. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Author: Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Hogdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, Garcia-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubinski, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, Garcia-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jimenez, A, Garcia, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, Koebel, M, Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Hogdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, Garcia-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubinski, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, Garcia-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jimenez, A, Garcia, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, and Koebel, M
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Published: 2018

33. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author: Block, MS, Vierkant, RA, Rambau, PF, Winham, SJ, Wagner, P, Traficante, N, Toloczko, A, Tiezzi, DG, Taran, FA, Sinn, P, Sieh, W, Sharma, R, Rothstein, JH, Ramon y Cajal, T, Paz-Ares, L, Oszurek, O, Orsulic, S, Ness, RB, Nelson, G, Modugno, F, Menkiszak, J, McGuire, V, McCauley, BM, Mack, M, Lubinski, J, Longacre, TA, Li, Z, Lester, J, Kennedy, CJ, Kalli, KR, Jung, AY, Johnatty, SE, Jimenez-Linan, M, Jensen, A, Intermaggio, MP, Hung, J, Herpel, E, Hernandez, BY, Hartkopf, AD, Harnett, PR, Ghatage, P, Garcia-Bueno, JM, Gao, B, Fereday, S, Eilber, U, Edwards, RP, de Sousa, CB, de Andrade, JM, Chudecka-Glaz, A, Chenevix-Trench, G, Cazorla, A, Brucker, SY, Alsop, J, Whittemore, AS, Steed, H, Staebler, A, Moysich, KB, Menon, U, Koziak, JM, Kommoss, S, Kjaer, SK, Kelemen, LE, Karlan, BY, Huntsman, DG, Hogdall, E, Gronwald, J, Goodman, MT, Gilks, B, Jose Garcia, M, Fasching, PA, de Fazio, A, Deen, S, Chang-Claude, J, dos Reis, FJC, Campbell, IG, Brenton, JD, Bowtell, DD, Benitez, J, Pharoah, PDP, Kobel, M, Ramus, SJ, Goode, EL, Block, MS, Vierkant, RA, Rambau, PF, Winham, SJ, Wagner, P, Traficante, N, Toloczko, A, Tiezzi, DG, Taran, FA, Sinn, P, Sieh, W, Sharma, R, Rothstein, JH, Ramon y Cajal, T, Paz-Ares, L, Oszurek, O, Orsulic, S, Ness, RB, Nelson, G, Modugno, F, Menkiszak, J, McGuire, V, McCauley, BM, Mack, M, Lubinski, J, Longacre, TA, Li, Z, Lester, J, Kennedy, CJ, Kalli, KR, Jung, AY, Johnatty, SE, Jimenez-Linan, M, Jensen, A, Intermaggio, MP, Hung, J, Herpel, E, Hernandez, BY, Hartkopf, AD, Harnett, PR, Ghatage, P, Garcia-Bueno, JM, Gao, B, Fereday, S, Eilber, U, Edwards, RP, de Sousa, CB, de Andrade, JM, Chudecka-Glaz, A, Chenevix-Trench, G, Cazorla, A, Brucker, SY, Alsop, J, Whittemore, AS, Steed, H, Staebler, A, Moysich, KB, Menon, U, Koziak, JM, Kommoss, S, Kjaer, SK, Kelemen, LE, Karlan, BY, Huntsman, DG, Hogdall, E, Gronwald, J, Goodman, MT, Gilks, B, Jose Garcia, M, Fasching, PA, de Fazio, A, Deen, S, Chang-Claude, J, dos Reis, FJC, Campbell, IG, Brenton, JD, Bowtell, DD, Benitez, J, Pharoah, PDP, Kobel, M, Ramus, SJ, and Goode, EL
Abstract: OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
Published: 2018

34. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Kelemen, LE, Earp, M, Fridley, BL, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Lambrechts, D, Lambrechts, S, Van Nieuwenhuysen, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Behrens, S, Moysich, KB, Cannioto, R, Lele, S, Odunsi, K, Goodman, MT, Shvetsov, YB, Thompson, PJ, Wilkens, LR, Doerk, T, Antonenkova, N, Bogdanova, N, Hillemanns, P, Runnebaum, IB, du Bois, A, Harter, P, Heitz, F, Schwaab, I, Butzow, R, Pelttari, LM, Nevanlinna, H, Modugno, F, Edwards, RP, Kelley, JL, Ness, RB, Karlan, BY, Lester, J, Orsulic, S, Walsh, C, Kjaer, SK, Jensen, A, Cunningham, JM, Vierkant, RA, Giles, GG, Bruinsma, F, Southey, MC, Hildebrandt, MAT, Liang, D, Lu, K, Wu, X, Sellers, TA, Levine, DA, Schildkraut, JM, Iversen, ES, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Bandera, EV, Olson, SH, Orlow, I, Thomsen, LCV, Bjorge, L, Krakstad, C, Tangen, IL, Kiemeney, LA, Aben, KKH, Massuger, LFAG, van Altena, AM, Pejovic, T, Bean, Y, Kellar, M, Cook, LS, Le, ND, Brooks-Wilson, A, Gronwald, J, Cybulski, C, Jakubowska, A, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Hogdall, E, Engelholm, SA, Hogdall, C, Lundvall, L, Nedergaard, L, Pharoah, PDP, Dicks, E, Song, H, Tyrer, JP, McNeish, I, Siddiqui, N, Carty, K, Glasspool, R, Paul, J, Campbell, IG, Eccles, D, Whittemore, AS, McGuire, V, Rothstein, JH, Sieh, W, Narod, SA, Phelan, CM, McLaughlin, JR, Risch, HA, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Gentry-Maharaj, A, Ramus, SJ, Wu, AH, Pearce, CL, Lee, AW, Pike, MC, Kupryjanczyk, J, Podgorska, A, Plisiecka-Halasa, J, Sawicki, W, Goode, EL, Berchuck, A, Kelemen, LE, Earp, M, Fridley, BL, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Lambrechts, D, Lambrechts, S, Van Nieuwenhuysen, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Behrens, S, Moysich, KB, Cannioto, R, Lele, S, Odunsi, K, Goodman, MT, Shvetsov, YB, Thompson, PJ, Wilkens, LR, Doerk, T, Antonenkova, N, Bogdanova, N, Hillemanns, P, Runnebaum, IB, du Bois, A, Harter, P, Heitz, F, Schwaab, I, Butzow, R, Pelttari, LM, Nevanlinna, H, Modugno, F, Edwards, RP, Kelley, JL, Ness, RB, Karlan, BY, Lester, J, Orsulic, S, Walsh, C, Kjaer, SK, Jensen, A, Cunningham, JM, Vierkant, RA, Giles, GG, Bruinsma, F, Southey, MC, Hildebrandt, MAT, Liang, D, Lu, K, Wu, X, Sellers, TA, Levine, DA, Schildkraut, JM, Iversen, ES, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Bandera, EV, Olson, SH, Orlow, I, Thomsen, LCV, Bjorge, L, Krakstad, C, Tangen, IL, Kiemeney, LA, Aben, KKH, Massuger, LFAG, van Altena, AM, Pejovic, T, Bean, Y, Kellar, M, Cook, LS, Le, ND, Brooks-Wilson, A, Gronwald, J, Cybulski, C, Jakubowska, A, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Hogdall, E, Engelholm, SA, Hogdall, C, Lundvall, L, Nedergaard, L, Pharoah, PDP, Dicks, E, Song, H, Tyrer, JP, McNeish, I, Siddiqui, N, Carty, K, Glasspool, R, Paul, J, Campbell, IG, Eccles, D, Whittemore, AS, McGuire, V, Rothstein, JH, Sieh, W, Narod, SA, Phelan, CM, McLaughlin, JR, Risch, HA, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Gentry-Maharaj, A, Ramus, SJ, Wu, AH, Pearce, CL, Lee, AW, Pike, MC, Kupryjanczyk, J, Podgorska, A, Plisiecka-Halasa, J, Sawicki, W, Goode, EL, and Berchuck, A
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

35. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, SC, Nagle, CM, Thrift, AP, Pharoah, PDP, Ewing, A, Pearce, CL, Zheng, W, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Jung, AY, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Doerk, T, Park-Simon, T-W, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Karlan, BY, Lester, J, Orsulic, S, Rimel, BJ, Kjaer, SK, Hogdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LCV, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubinski, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Hogdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, Sieh, W, McGuire, V, Rothstein, JH, Narod, SA, Phelan, C, Risch, HA, McLaughlin, JR, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pike, MC, Tseng, C-C, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Budzilowska, A, Rzepecka, IK, Webb, PM, Dixon-Suen, SC, Nagle, CM, Thrift, AP, Pharoah, PDP, Ewing, A, Pearce, CL, Zheng, W, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Jung, AY, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Doerk, T, Park-Simon, T-W, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Karlan, BY, Lester, J, Orsulic, S, Rimel, BJ, Kjaer, SK, Hogdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LCV, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubinski, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Hogdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, Sieh, W, McGuire, V, Rothstein, JH, Narod, SA, Phelan, C, Risch, HA, McLaughlin, JR, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pike, MC, Tseng, C-C, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Budzilowska, A, Rzepecka, IK, and Webb, PM
Abstract: BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Published: 2018

36. Genomic alterations accompanying tumour evolution in colorectal cancer:tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

Author: Mogensen, M B, Rossing, M, Østrup, O, Larsen, P N, Heiberg Engel, P J, Jørgensen, L N, Hogdall, E V, Eriksen, J, Ibsen, P, Jess, P, Grauslund, M, Nielsen, H J, Nielsen, F C, Vainer, B, Osterlind, K, Mogensen, M B, Rossing, M, Østrup, O, Larsen, P N, Heiberg Engel, P J, Jørgensen, L N, Hogdall, E V, Eriksen, J, Ibsen, P, Jess, P, Grauslund, M, Nielsen, H J, Nielsen, F C, Vainer, B, and Osterlind, K
Abstract: BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational
Published: 2018

37. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author: Glubb, DM, Johnatty, SE, Quinn, MCJ, O'Mara, TA, Tyrer, JP, Gao, B, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Thompson, PJ, Doerk, T, Duerst, M, Modungo, F, Moysich, K, Heitz, F, du Bois, A, Pfisterer, J, Hillemanns, P, Karlan, BY, Lester, J, Goode, EL, Cunningham, JM, Winham, SJ, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Salvesen, HB, Bjorge, L, Webb, PM, Grant, P, Pejovic, T, Moffitt, M, Hogdall, CK, Hogdall, E, Paul, J, Glasspool, R, Bernardini, M, Tone, A, Huntsman, D, Woo, M, deFazio, A, Kennedy, CJ, Pharoah, PDP, MacGregor, S, Chenevix-Trench, G, Grp, AGOS, Grp, AOCS, Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: meta-analysis, genetic association, Oncology and Carcinogenesis, AGO Study Group, ovarian cancer outcome, gene regulation, health care economics and organizations
Abstract: We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p
Published: 2017

38. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author: Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Szender, JB, Eng, KH, Modugno, F, Ness, RB, LaMonte, MJ, Friel, G, Segal, BH, Odunsi, K, Mayor, P, Zsiros, E, Schmalfeldt, B, Klapdor, R, Doerk, T, Hillemanns, P, Kelemen, LE, Kobel, M, Steed, H, de Fazio, A, Jordan, SJ, Nagle, CM, Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Edwards, R, Matsuo, K, Mizuno, M, Karlan, BY, Kjaer, SK, Hogdall, E, Jensen, A, Schildkraut, JM, Terry, KL, Cramer, DW, Bandera, EV, Paddock, LE, Kiemeney, LA, Massuger, LF, Kupryjanczyk, J, Berchuck, A, Chang-Claude, J, Diergaarde, B, Webb, PM, Moysich, KB, Grp, AOCS, and Consortium, OCA
Subjects: Australian Ovarian Cancer Study Group, Risk, Adult, Heart Diseases, Epidemiology, Ovarian Cancer Association Consortium, Adrenergic beta-Antagonists, Oncology and Carcinogenesis, Medications, Cardiovascular, Disease-Free Survival, Rare Diseases, Clinical Research, Diabetes Mellitus, Genetics, Humans, Insulin, Hypoglycemic Agents, Mortality, Aged, Cancer, Ovarian Neoplasms, screening and diagnosis, Beta blockers, Ovarian cancer prognosis, Diabetes, Middle Aged, Ovarian Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Survival Rate, Detection, Good Health and Well Being, Hypertension, Public Health and Health Services, Female
Abstract: PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.
Published: 2017

39. Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium

Author: Dixon, SC, Nagle, CM, Wentzensen, N, Trabert, B, Beeghly-Fadiel, A, Schildkraut, JM, Moysich, KB, deFazio, A, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Ness, RB, Edwards, RP, Jensen, A, Kjaer, SK, Hogdall, E, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Bandera, EV, Paddock, LE, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Pike, MC, Webb, PM, Grp, AOCS, and Consortium, OCA
Subjects: nonsteroidal anti-inflammatory drugs, ovarian cancer, aspirin, paracetamol, pooled analysis, survival, NSAID, acetaminophen
Published: 2017

40. Risk of Ovarian Cancer and the NF-? B Pathway: Genetic Association with IL1A and TNFSF10

Author: Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, L. F. A. G., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., Van Altena, A. M., van den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A. T., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D. P., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., and Goode, E. L.
Published: 2014
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41. National coverage of biological materials for translational research in the Danish cancerbiobank (RBGB) and of corresponding clinical data in the Danish Gynecological Cancer Database (DGCD)

Author: Høgdall, E., Schnack, T., Steffensen, K.D., Jochumsen, K., Kahr, H.S., Ingerslev, K., Antonsen, S.L., Christensen, I.J., and Hogdall, C.
Published: 2020
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42. Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies

Author: Praestegaard, C., Jensen, A., Jensen, S.M., Nielsen, T.S., Webb, P.M., Nagle, C.M., Defazio, A., Hogdall, E., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R., Matsuo, K., Hosono, S., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L.E., Massuger, L.F.A.G., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M., Lee, A.W., Sutphen, R., Chang-Claude, J., Risch, H.A., Kjaer, S.K., Praestegaard, C., Jensen, A., Jensen, S.M., Nielsen, T.S., Webb, P.M., Nagle, C.M., Defazio, A., Hogdall, E., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R., Matsuo, K., Hosono, S., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L.E., Massuger, L.F.A.G., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M., Lee, A.W., Sutphen, R., Chang-Claude, J., Risch, H.A., and Kjaer, S.K.
Abstract: Contains fulltext : 174714.pdf (publisher's version ) (Closed access), Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.
Published: 2017

43. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium

Author: Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., and Moysich, K.B.
Abstract: Contains fulltext : 177359.pdf (publisher's version ) (Closed access), Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. (c)2017 AACR.
Published: 2017

44. Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies

Author: Rasmussen, C.B., Kjaer, S.K., Albieri, V., Bandera, E.V., Doherty, J.A., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K.B., Ness, R.B., Edwards, R.P., Schildkraut, J.M., Berchuck, A., Olson, S.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Narod, S.A., Phelan, C.M., Anton-Culver, H., Ziogas, A., Wu, A.H., Pearce, C.L., Risch, H.A., Jensen, A., Rasmussen, C.B., Kjaer, S.K., Albieri, V., Bandera, E.V., Doherty, J.A., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K.B., Ness, R.B., Edwards, R.P., Schildkraut, J.M., Berchuck, A., Olson, S.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Narod, S.A., Phelan, C.M., Anton-Culver, H., Ziogas, A., Wu, A.H., Pearce, C.L., Risch, H.A., and Jensen, A.
Abstract: Contains fulltext : 169777.pdf (publisher's version ) (Closed access), Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.
Published: 2017

45. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author: Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., and Moysich, K.B.
Abstract: Contains fulltext : 174140.pdf (publisher's version ) (Closed access), PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidi
Published: 2017

46. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author: Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., Lawrenson, K., Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., and Lawrenson, K.
Abstract: Contains fulltext : 170527.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 x 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Published: 2017

47. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author: Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, Lawrenson, K, Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, and Lawrenson, K
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Published: 2017

48. Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies

Author: Praestegaard, C, Jensen, A, Jensen, SM, Nielsen, TSS, Webb, PM, Nagle, CM, DeFazio, A, Hogdall, E, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, R, Matsuo, K, Hosono, S, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, LE, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, M, Lee, AW, Sutphen, R, Chang-Claude, J, Risch, HA, Kjaer, SK, Praestegaard, C, Jensen, A, Jensen, SM, Nielsen, TSS, Webb, PM, Nagle, CM, DeFazio, A, Hogdall, E, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, R, Matsuo, K, Hosono, S, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, LE, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, M, Lee, AW, Sutphen, R, Chang-Claude, J, Risch, HA, and Kjaer, SK
Abstract: Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.
Published: 2017

49. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types

Author: Kar, SP, Beesley, J, Al Olama, AA, Michailidou, K, Tyrer, J, Kote-Jarai, ZA, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Hogdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Cramer, DW, Neal, DE, Eccles, D, Flesch-Janys, D, Velez Edwards, DR, Wokozorczyk, D, Levine, DA, Yannoukakos, D, Sawyer, EJ, Bandera, EV, Poole, EM, Goode, EL, Khusnutdinova, E, Hogdall, E, Song, F, Bruinsma, F, Heitz, F, Modugno, F, Hamdy, FC, Wiklund, F, Giles, GG, Olsson, H, Wildiers, H, and Ulmer, HU
Abstract: © 2016 American Association for Cancer Research. Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
Published: 2016

50. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author: Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 4 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA [ 5 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 6 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 7 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 8 ] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia [ 9 ] KConFab Kathleen Cuningham Consortium Res Familia, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia [ 10 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 11 ] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia [ 12 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 13 ] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia [ 14 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 15 ] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia [ 16 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 17 ] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands [ 18 ] Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Coordinating Ctr, Amsterdam, Netherlands [ 19 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Ostetr, D-91054 Erlangen, Germany [ 20 ] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA [ 21 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 22 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England [ 23 ] Guys Hosp, Kings Coll London, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 24 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England [ 25 ] Royal Marsden NHS Fdn Trust, London, England [ 26 ] Univ Coll London Elizabeth Garrett Anderson EGA, Inst Womens Hlth, Womens Canc, London, England [ 27 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 28 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 29 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 30 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 31 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 32 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 33 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 34 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 35 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 36 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 37 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 38 ] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA [ 39 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 40 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 41 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 42 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 43 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 44 ] Natl Inst Hlth & Med Res, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc, INSERM,U1018, Villejuif, France [ 45 ] Univ Paris Sud, Villejuif, France [ 46 ] UNICANCER Genet Grp, GEMO Study Natl Canc Genet Network, Paris, France [ 47 ] Inst Curie, Dept Tumour Biol, Paris, France [ 48 ] INSERM, U830, Inst Curie, Paris, France [ 49 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 50 ] Univ Lyon, Ctr Rech Cancerol Lyon, INSERM,U1052, CNRS UMR 5286, Lyon, France [ 51 ] Hosp Civils Pyon, Ctr Leon Berard, Unite Mixte Genet Constitutionelle Canc Frequents, Lyon, France [ 52 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 53 ] Hop Univ Strasbourg, CHRU Nouvel, Lab Diagnost Genet, Hop Civil, Strasbourg, France [ 54 ] Hop Univ Strasbourg, CHRU Nouvel, Serv Oncohematol, Hop Civil, Strasbourg, France [ 55 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 56 ] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, Herlev, Denmark [ 57 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 58 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark [ 59 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 60 ] Danish Canc Soc, Dept Virus Lifestyle & Genes, Res Ctr, Copenhagen, Denmark [ 61 ] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark [ 62 ] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark [ 63 ] Aalborg Univ Hosp, Dept Biochem, Sect Mol Diagnost, Aalborg, Denmark [ 64 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 65 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain [ 66 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genotyping Unit CEGEN, Madrid, Spain [ 67 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 68 ] IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain [ 69 ] IdISSC, Hosp Clin San Carlos, Dept Oncol, Madrid, Spain [ 70 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona, Spain [ 71 ] Univ Autonoma Barcelona, E-08193 Barcelona, Spain [ 72 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain [ 73 ] Catalan Inst Oncol, IDIBGI Inst Invest Biomed Girona, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 74 ] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA [ 75 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA [ 76 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 77 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 78 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA [ 79 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 80 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 81 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 82 ] Univ Calif San Francisco, Helen Diller Family Canc Ctr, Canc Risk Program, San Francisco, CA 94143 USA [ 83 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 84 ] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA [ 85 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 86 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA [ 87 ] Roswell Pk Ctr Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY USA [ 88 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 89 ] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA [ 90 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 91 ] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA [ 92 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 93 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Ctr, Philadelphia, PA 19104 USA [ 94 ] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA [ 95 ] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA [ 96 ] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA [ 97 ] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA [ 98 ] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA [ 99 ] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA [ 100 ] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA [ 101 ] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA [ 102 ] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 103 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA [ 104 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA [ 105 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 106 ] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany [ 107 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 108 ] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany [ 109 ] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany [ 110 ] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany [ 111 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy [ 139 ] Aviano Natl Canc Inst, CRO, Div Expt Oncol, Aviano, Italy [ 140 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 141 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy [ 142 ] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy [ 143 ] ULSS5 Ovest Vicentino, UOC Oncol, Veneto, Italy [ 144 ] Portugese Oncol Inst, Dept Genet, Oporto, Portugal [ 145 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 146 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 147 ] Univ Hosp Pisa, Pisa, Italy [ 148 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 149 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 150 ] Prince Wales Hosp, Sydney, NSW, Australia [ 151 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 152 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 153 ] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada [ 154 ] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada [ 155 ] Univ Cambridge, Sch Med, Cambridge, England [ 156 ] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada [ 157 ] Univ Laval, Quebec City, PQ, Canada [ 158 ] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England [ 159 ] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada [ 160 ] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 161 ] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway [ 162 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 163 ] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway [ 164 ] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway [ 165 ] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA [ 166 ] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA [ 167 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Div Epidemiol,Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA [ 168 ] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 169 ] Univ Oulu, Bioctr Oulu, Oulu, Finland [ 170 ] Northern Finland Lab Ctr Nordlab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 171 ] Erasmus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands [ 172 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands [ 173 ] Mt Sinai Hosp, Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada [ 174 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 175 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 176 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 177 ] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada [ 178 ] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands [ 179 ] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands [ 180 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 181 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA [ 182 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 183 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 184 ] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland [ 185 ] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland [ 186 ] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland [ 187 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 188 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 189 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 190 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 191 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 192 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia [ 193 ] Univ Malaya, Med Ctr, Fac Med, Canc Res Inst, Kuala Lumpur, Malaysia [ 194 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 195 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan [ 196 ] Univ Malaya, Med Ctr, Dept Obstet & Gynecol, Kuala Lumpur, Malaysia [ 197 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 198 ] Masaryk Mem Canc Inst & Med Fac, Brno, Czech Republic [ 199 ] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria [ 200 ] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria [ 201 ] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel [ 202 ] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 203 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 204 ] B Rappaport Fac Med, Haifa, Israel [ 205 ] NN Petrov Inst Oncol, St Petersburg, Russia [ 206 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 207 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 208 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 209 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 210 ] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA [ 211 ] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA [ 212 ] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA [ 213 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands [ 214 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands [ 215 ] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA [ 216 ] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA [ 217 ] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA [ 218 ] Lund Univ, Dept Oncol, Lund, Sweden [ 219 ] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden [ 220 ] Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA [ 221 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 222 ] Univ Lund Hosp, Ctr Oncol, Reg Tumour Registry, S-22185 Lund, Sweden [ 223 ] Univ Sheffield, Sheffield Canc Res Dept Oncol, Sheffield, S Yorkshire, England [ 224 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 225 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia [ 226 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 227 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 228 ] Univ Iceland, Sch Med, Reykjavik, Iceland [ 229 ] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland [ 230 ] Inst Oncol, Warsaw, Poland [ 231 ] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Nucl & Radiol Sci & Technol, Energy & Safety, Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract: Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016

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