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1. Incidence of endometrial cancer in BRCA mutation carriers

Author: Kotsopoulos, J, Lubinski, J, Huzarski, T, Bychkovsky, B, Moller, P, Kim, R, Tung, N, Eisen, A, Foulkes, W, Singer, C, Aeilts, A, Neuhausen, S, Bordeleau, L, Karlan, B, Fruscio, R, Eng, C, Olopade, O, Zakalik, D, Couch, F, y Cajal, T, Sun, P, Gronwald, J, Narod, S, Kotsopoulos J., Lubinski J., Huzarski T., Bychkovsky B. L., Moller P., Kim R. H., Tung N., Eisen A., Foulkes W., Singer C. F., Aeilts A., Neuhausen S. L., Bordeleau L., Karlan B., Fruscio R., Eng C., Olopade O., Zakalik D., Couch F., y Cajal T. R., Sun P., Gronwald J., Narod S. A., Kotsopoulos, J, Lubinski, J, Huzarski, T, Bychkovsky, B, Moller, P, Kim, R, Tung, N, Eisen, A, Foulkes, W, Singer, C, Aeilts, A, Neuhausen, S, Bordeleau, L, Karlan, B, Fruscio, R, Eng, C, Olopade, O, Zakalik, D, Couch, F, y Cajal, T, Sun, P, Gronwald, J, Narod, S, Kotsopoulos J., Lubinski J., Huzarski T., Bychkovsky B. L., Moller P., Kim R. H., Tung N., Eisen A., Foulkes W., Singer C. F., Aeilts A., Neuhausen S. L., Bordeleau L., Karlan B., Fruscio R., Eng C., Olopade O., Zakalik D., Couch F., y Cajal T. R., Sun P., Gronwald J., and Narod S. A.
Abstract: Objective: Whether or not women who harbor a germline pathogenic variant (‘mutation’) in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. Methods: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. Results: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8–76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two–fold increased risk (HR = 2.24; 95% CI 1.10–4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). Conclusions: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.
Published: 2024

2. Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis

Author: Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., Cohen S., Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., and Cohen S.
Abstract: Background: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. Methods: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. Results: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05–1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. Conclusions: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.
Published: 2024

3. Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, and Narod, Steven A
Abstract: IMPORTANCE Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. OBJECTIVE To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. DESIGN, SETTING, AND PARTICIPANTS In this international, longitudinal cohort study ofwomen with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. EXPOSURES Self-reported bilateral oophorectomy (with or without salpingectomy). MAIN OUTCOMES AND MEASURES All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. RESULTS There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estima
Published: 2024

4. MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A
Abstract: IMPORTANCE Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. OBJECTIVE To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. DESIGN, SETTING, AND PARTICIPANTS Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. EXPOSURES Entrance into an MRI surveillance program. MAIN OUTCOMES AND MEASURES Cox proportional hazards modelingwas used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. RESULTS A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0
Published: 2024

5. Prognostic gene expression signature for high-grade serous ovarian cancer

Author: Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier,a, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O’Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Millstein, J., Budden, T., Goode, E.L., Anglesio, M.S., Talhouk, A., Intermaggio, M.P., Leong, H.S., Chen, S., Elatre, W., Gilks, B., Nazeran, T., Volchek, M., Bentley, R.C., Wang, C., Chiu, D.S., Kommoss, S., Leung, S.C.Y., Senz, J., Lum, A., Chow, V., Sudderuddin, H., Mackenzie, R., George, J., Steed, H., Koziak, J.M., Köbel, M., McNeish, I.A., Goranova, T., Ennis, D., Macintyre, G., Silva De Silva, D., Ramón y Cajal, T., García-Donas, J., Hernando Polo, S., Rodriguez, G.C., Cushing-Haugen, K.L., Harris, H.R., Greene, C.S., Zelaya, R.A., Behrens, S., Fortner, R.T., Sinn, P., Herpel, E., Lester, J., Lubiński, J., Oszurek, O., Tołoczko, A., Cybulski, C., Menkiszak, J., Pearce, C.L., Pike, M.C., Tseng, C., Alsop, J., Rhenius, V., Song, H., Jimenez-Linan, M., Piskorz, A.M., Gentry-Maharaj, A., Karpinskyj, C., Widschwendter, M., Singh, N., Kennedy, C.J., Harnett, P.R., Gao, B., Johnatty, S.E., Sayer, R., Boros, J., Winham, S.J., Keeney, G.L., Kaufmann, S.H., Larson, M.C., Luk, H., Hernandez, B.Y., Thompson, P.J., Wilkens, L.R., Carney, M.E., Trabert, B., Lissowska, J., Brinton, L., Sherman, M.E., Bodelon, C., Hinsley, S., Lewsley, L.A., Glasspool, R., Banerjee, S.N., Stronach, E.A., Haluska, P., Ray-Coquard, I., Mahner, S., Winterhoff, B., Slamon, D., Levine, D.A., Kelemen, L.E., Benitez, J., Chang-Claude, J., Gronwald, J., Wu, A.H., Menon, U., Goodman, M.T., Schildkraut, J.M., Wentzensen, N., Brown, R., Berchuck, A., deFazio, A., Gayther, S.A., García, M.J., Henderson, M.J., Rossing, M.A., Beeghly-Fadiel, A., Fasching, P.A., Orsulic, S., Karlan, B.Y., Konecny, G.E., Huntsman, D.G., Bowtell, D.D., Brenton, J.D., Doherty, J.A., Pharoah, P.D.P., and Ramus, S.J.
Published: 2020
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6. 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

7. Erratum: Correction to: Survival from breast cancer in women with a BRCA2 mutation by treatment (British journal of cancer (2021) 124 9 (1524-1532))

Author: Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., Narod S. A., Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., and Narod S. A.
Published: 2023

8. Clinical Utility of MLPA and QF-PCR Techniques in the Genetic Testing of Miscarriages

Author: Bernatowicz, K., Zimowski, J., Łaczmańska, I., Piotrowski, K., Kashyap, A., Bednarska-Makaruk, M., Sąsiadek, M., and Gronwald, J.
Published: 2019
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9. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Author: Antoniou, AC, Cunningham, AP, Peto, J, Evans, DG, Lalloo, F, Narod, SA, Risch, HA, Eyfjord, JE, Hopper, JL, Southey, MC, Olsson, H, Johannsson, O, Borg, A, Passini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tryggvadottir, L, Syrjakoski, K, Kallioniemi, O-P, Eerola, H, Nevanlinna, H, Pharoah, PDP, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Cancer, Genetics, Genetic Testing, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 2.6 Resources and infrastructure (aetiology), Adult, Age Factors, Aged, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening, Genetic Predisposition to Disease, Humans, Middle Aged, Models, Genetic, Mutation, Neoplasms, Second Primary, Ovarian Neoplasms, BRCA1, BRCA2, cancer risk model, genetic testing, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
Published: 2008

10. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Author: Antoniou, AC, Pharoah, PDP, Narod, S, Risch, HA, Eyfjord, JE, Hopper, JL, Olsson, H, Johannsson, O, Borg, A, Pasini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tulinius, H, Thorlacius, S, Eerola, H, Nevanlinna, H, Syrjäkoski, K, Kallioniemi, O-P, Thompson, D, Evans, C, Peto, J, Lalloo, F, Evans, DG, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Breast Neoplasms, Female, Founder Effect, Genes, BRCA1, Genes, BRCA2, Heterozygote, Humans, Incidence, Jews, Meta-Analysis as Topic, Middle Aged, Mutation, Ovarian Neoplasms, Penetrance, Prevalence, Risk Assessment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
Published: 2005

11. The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

Author: Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., Narod S. A., Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., and Narod S. A.
Abstract: Background: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant. Methods: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method. Results: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%. Conclusion: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.
Published: 2022

12. Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

Author: Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., Cohen S., Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., and Cohen S.
Abstract: Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.
Published: 2022

13. Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Author: Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, Garsed, DW, Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, and Garsed, DW
Abstract: BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carr
Published: 2023

14. 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

15. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author: Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, Harnett, P, Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, and Harnett, P
Abstract: BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

16. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, Brenton, JD, Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, and Brenton, JD
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

17. Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation

Author: Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A
Abstract: Purpose: Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. Methods: We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. Results: There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40–1.03; P = 0.07). Conclusion: Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.
Published: 2023

18. CERVICAL CANCER SCREENING IN PHC ORGANIZATION IN POLAND: EP386

Author: Prusaczyk, A, Prokurat, E, Szafraniec-Burylo, S, Bidzinski, M, and Gronwald, J
Published: 2019
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19. 265 Evaluation of the constructed the device along with the software for digital archiving, sending the data and supporting the diagnosis of cervical cancer

Author: Gronwald, J, Lasyk, Ł, Barbasz, J, Prusaczyk, A, Żuk, P, Włodarczyk, T, Prokurat, E, Olszewski, W, and Bidziński, M
Published: 2019
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20. Serum selenium levels predict survival after breast cancer

Author: Lubinski, J., Marciniak, W., Muszynska, M., Huzarski, T., Gronwald, J., Cybulski, C., Jakubowska, A., Debniak, T., Falco, M., Kladny, J., Kotsopoulos, J., Sun, P., and Narod, S. A.
Published: 2017
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21. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author: Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., and Bordeleau L.
Abstract: Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.
Published: 2021

22. The impact of oophorectomy on survival after breast cancer in BRCA1-positive breast cancer patients

Author: Huzarski, T., Byrski, T., Gronwald, J., Cybulski, C., Oszurek, O., Szwiec, M., Gugała, K., Stawicka, M., Morawiec, Z., Mierzwa, T., Falco, M., Janiszewska, H., Kilar, E., Marczyk, E., Kozak-Klonowska, B., Siołek, M., Surdyka, D., Wiśniowski, R., Posmyk, M., Domagała, P., Sun, P., Lubiński, J., Narod, S. A., and The Polish Breast Cancer Consortium
Published: 2016
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23. 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, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, 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, YE, 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, Dörk, T, Du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, RY, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Van Der Hout, AH, Isaacs, C, Jakubowska, A, James, PA, Dareng, EO [0000-0003-0802-419X], Tyrer, JP [0000-0003-3724-4757], Barnes, DR [0000-0002-3781-7570], Yang, X [0000-0003-0037-3790], Andrulis, IL [0000-0002-4226-6435], Augustinsson, A [0000-0003-3415-0536], Barrowdale, D [0000-0003-1661-3939], Bonanni, B [0000-0003-3589-2128], Brenton, JD [0000-0002-5738-6683], Butzow, R [0000-0003-4366-5099], Chanock, SJ [0000-0002-2324-3393], Claes, KBM [0000-0003-0841-7372], de la Hoya, M [0000-0002-8113-1410], de Putter, R [0000-0001-9410-8941], Dennis, J [0000-0003-4591-1214], Devilee, P [0000-0002-8023-2009], du Bois, A [0000-0002-8477-506X], Machackova, E [0000-0002-0246-1471], Giles, GG [0000-0003-4946-9099], Godwin, AK [0000-0002-3987-9580], Greene, MH [0000-0003-1852-9239], Heitz, F [0000-0002-2412-0352], Hulick, PJ [0000-0001-8397-4078], Jakubowska, A [0000-0002-5650-0501], James, PA [0000-0002-4361-4657], and Apollo - University of Cambridge Repository
Subjects: Rare Diseases, FOS: Biological sciences, Prevention, Genetics, 32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis, 3105 Genetics, 31 Biological Sciences, Ovarian Cancer, Cancer
Abstract: Funder: Funding details are provided in the Supplementary Material, 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 ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. 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 ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,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
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24. 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

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

Author: Dareng, E.O., Tyrer, J.P., Barnes, D.R., Jones, M.R., Yang, X, Aben, K.K.H., Adank, M.A., Agata, S., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Aravantinos, G., Arun, B.K., Augustinsson, A., Balmaña, J., Bandera, E.V., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Bjorge, L., Black, A., Bogdanova, N.V., Bonanni, B., Borg, A., Brenton, J.D., Budzilowska, A., Butzow, R., Buys, S.S., Cai, H., Caligo, M.A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S.J., Chen, K., Chiew, Y.E., Chung, W.K., Claes, K.B.M., Colonna, S., Cook, L.S., Couch, F.J., Daly, M.B., Dao, F., Davies, E., Hoya, M. de la, Putter, R. de, Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dörk, T., Bois, A. du, Dürst, M., Eccles, D.M., Eliassen, H.A., Engel, C., Evans, G.D., Fasching, P.A., Flanagan, J.M., Fortner, R.T., Machackova, E., Friedman, E., Ganz, P.A., Garber, J., Gensini, F., Giles, G.G., Glendon, G., Godwin, A.K., Goodman, M.T., Greene, M.H., Gronwald, J., Hahnen, E., Haiman, C.A., Håkansson, N., Hamann, U., Hansen, T.V., Harris, H.R., Hartman, M, Heitz, F., Hildebrandt, M.A., Høgdall, E., Høgdall, C.K., Hopper, J.L., Huang, R.Y., Huff, C., Hulick, P.J., Huntsman, D.G., Imyanitov, E.N., Isaacs, C., Jakubowska, A., James, P.A., Kiemeney, L.A.L.M., Altena, A.M. van, Janavicius, R., Antoniou, A.C., Pharoah, P.D., Dareng, E.O., Tyrer, J.P., Barnes, D.R., Jones, M.R., Yang, X, Aben, K.K.H., Adank, M.A., Agata, S., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Aravantinos, G., Arun, B.K., Augustinsson, A., Balmaña, J., Bandera, E.V., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Bjorge, L., Black, A., Bogdanova, N.V., Bonanni, B., Borg, A., Brenton, J.D., Budzilowska, A., Butzow, R., Buys, S.S., Cai, H., Caligo, M.A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S.J., Chen, K., Chiew, Y.E., Chung, W.K., Claes, K.B.M., Colonna, S., Cook, L.S., Couch, F.J., Daly, M.B., Dao, F., Davies, E., Hoya, M. de la, Putter, R. de, Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dörk, T., Bois, A. du, Dürst, M., Eccles, D.M., Eliassen, H.A., Engel, C., Evans, G.D., Fasching, P.A., Flanagan, J.M., Fortner, R.T., Machackova, E., Friedman, E., Ganz, P.A., Garber, J., Gensini, F., Giles, G.G., Glendon, G., Godwin, A.K., Goodman, M.T., Greene, M.H., Gronwald, J., Hahnen, E., Haiman, C.A., Håkansson, N., Hamann, U., Hansen, T.V., Harris, H.R., Hartman, M, Heitz, F., Hildebrandt, M.A., Høgdall, E., Høgdall, C.K., Hopper, J.L., Huang, R.Y., Huff, C., Hulick, P.J., Huntsman, D.G., Imyanitov, E.N., Isaacs, C., Jakubowska, A., James, P.A., Kiemeney, L.A.L.M., Altena, A.M. van, Janavicius, R., Antoniou, A.C., and Pharoah, P.D.
Abstract: Item does not contain fulltext, 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

26. Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)

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, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, 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, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, 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, Lubinski, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, 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, OI, 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, Terry, MB, 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, Van 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, JM, 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, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, 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, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, 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, Lubinski, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, 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, OI, 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, Terry, MB, 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, Van 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, JM, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Published: 2022

27. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., Jones, M.R., DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., and Jones, M.R.
Abstract: Item does not contain fulltext, BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Published: 2022

28. 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

29. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, Jones, MR, DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, and Jones, MR
Abstract: BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Published: 2022

30. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

Author: Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, Anglesio, MS, Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, and Anglesio, MS
Published: 2022

31. Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: a Reappraisal

Author: Kotsopoulos, J, Lubiński, J, Gronwald, J, Menkiszak, J, Mccuaig, J, Metcalfe, K, Foulkes, W, Neuhausen, S, Sun, S, Karlan, B, Eisen, A, Tung, N, Olopade, O, Couch, F, Huzarski, T, Senter, L, Bordeleau, L, Singer, C, Eng, C, Fruscio, R, Pal, T, Sun, P, Narod, S, Kotsopoulos, Joanne, Lubiński, Jan, Gronwald, Jacek, Menkiszak, Janusz, McCuaig, Jeanna, Metcalfe, Kelly, Foulkes, William D, Neuhausen, Susan L, Sun, Sophie, Karlan, Beth Y, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo I, Couch, Fergus J, Huzarski, Tomasz, Senter, Leigha, Bordeleau, Louise, Singer, Christian F, Eng, Charis, Fruscio, Robert, Pal, Tuya, Sun, Ping, Narod, Steven A, Kotsopoulos, J, Lubiński, J, Gronwald, J, Menkiszak, J, Mccuaig, J, Metcalfe, K, Foulkes, W, Neuhausen, S, Sun, S, Karlan, B, Eisen, A, Tung, N, Olopade, O, Couch, F, Huzarski, T, Senter, L, Bordeleau, L, Singer, C, Eng, C, Fruscio, R, Pal, T, Sun, P, Narod, S, Kotsopoulos, Joanne, Lubiński, Jan, Gronwald, Jacek, Menkiszak, Janusz, McCuaig, Jeanna, Metcalfe, Kelly, Foulkes, William D, Neuhausen, Susan L, Sun, Sophie, Karlan, Beth Y, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo I, Couch, Fergus J, Huzarski, Tomasz, Senter, Leigha, Bordeleau, Louise, Singer, Christian F, Eng, Charis, Fruscio, Robert, Pal, Tuya, Sun, Ping, and Narod, Steven A
Abstract: Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n=4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34- 0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87-1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.
Published: 2022

32. The impact of an expanded genetic testing program and selective oophorectomy on the incidence of ovarian cancer in West Pomerania

Author: Menkiszak, J., Sopik, V., Chudecka‐Głaz, A., Domagała, W., Urasińska, E., Symonowicz, H., Majdanik, E., Waloszczyk, P., Sycz, K., Świniarska, M., Huzarski, T., Cybulski, C., Debniak, T., Oszurek, O., Lubinski, J., Narod, S.A., and Gronwald, J.
Published: 2017
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33. Resistance to PS II Inhibitor Herbicides

Author: Gronwald, J. W., De Prado, R., editor, Jorrín, J., editor, and García-Torres, L., editor
Published: 1997
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34. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients

Author: Byrski, T., Huzarski, T., Dent, R., Marczyk, E., Jasiowka, M., Gronwald, J., Jakubowicz, J., Cybulski, C., Wisniowski, R., Godlewski, D., Lubinski, J., and Narod, S. A.
Published: 2014
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35. Survival from breast cancer in patients with CHEK2 mutations

Author: Huzarski, T., Cybulski, C., Wokolorczyk, D., Jakubowska, A., Byrski, T., Gronwald, J., Domagała, P., Szwiec, M., Godlewski, D., Kilar, E., Marczyk, E., Siołek, M., Wiśniowski, R., Janiszewska, H., Surdyka, D., Sibilski, R., Sun, P., Lubiński, J., and Narod, S. A.
Published: 2014
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36. NOD2 variants and the risk of malignant melanoma

Author: Dȩbniak, T, Kurzawski, G, Huzarski, T, Byrski, T, Gronwald, J, Dȩbniak, B, Rozmiarek, A, Dziuba, I, Złowocka, E, Suchy, J, Górski, B, Cybulski, C, Mierzejewski, M, Masojć, B, Masoj, B, Mȩdrek, K, Oszurek, O, Oleg, O, and Lubiǹski, J
Published: 2005

37. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author: Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, and Bordeleau, L
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Heterozygote, medicine.medical_treatment, Ovariectomy, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, 03 medical and health sciences, Breast cancer screening, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Cumulative incidence, Genetic Predisposition to Disease, Prospective Studies, skin and connective tissue diseases, Prospective cohort study, Mastectomy, Aged, Aged, 80 and over, BRCA2 Protein, medicine.diagnostic_test, business.industry, BRCA1 Protein, Incidence, Oophorectomy, Cancer, Hormone replacement therapy (menopause), Middle Aged, BRCA1, medicine.disease, BRCA2, Prophylactic Surgery, 3. Good health, Prospective, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Female, business
Abstract: Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.
Published: 2020

38. Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

Author: Qian, F., Wang, S.F., Mitchell, J., McGuffog, L., Barrowdale, D., Leslie, G., Oosterwijk, J.C., Chung, W.K., Evans, D.G., Engel, C., Kast, K., Aalfs, C.M., Adank, M.A., Adlard, J., Agnarsson, B.A., Aittomaki, K., Alducci, E., Andrulis, I.L., Arun, B.K., Ausems, M.G.E.M., Azzollini, J., Barouk-Simonet, E., Barwell, J., Belotti, M., Benitez, J., Berger, A., Borg, A., Bradbury, A.R., Brunet, J., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Caputo, S.M., Chiquette, J., Claes, K.B.M., Collee, J.M., Couch, F.J., Coupier, I., Daly, M.B., Davidson, R., Diez, O., Domchek, S.M., Donaldson, A., Dorfling, C.M., Eeles, R., Feliubadalo, L., Foretova, L., Fowler, J., Friedman, E., Frost, D., Ganz, P.A., Garber, J., Garcia-Barberan, V., Glendon, G., Godwin, A.K., Garcia, E.B.G., Gronwald, J., Hahnen, E., Hamann, U., Henderson, A., Hendricks, C.B., Hopper, J.L., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Izquierdo, A., Jakubowska, A., Kaczmarek, K., Kang, E., Karlan, B.Y., Kets, C.M., Kim, S.W., Kim, Z., Kwong, A., Laitman, Y., Lasset, C., Lee, M.H., Lee, J.W., Lee, J., Lester, J., Lesueur, F., Loud, J.T., Lubinski, J., Mebirouk, N., Meijers-Heijboer, H.E.J., Meindl, A., Miller, A., Montagna, M., Mooij, T.M., Morrison, P.J., Mouret-Fourme, E., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Niederacher, D., Nielsen, F.C., Nussbaum, R.L., Offit, K., Olah, E., Ong, K.R., Ottini, L., Park, S.K., Peterlongo, P., Pfeiler, G., Phelan, C.M., Poppe, B., Pradhan, N., Radice, P., Ramus, S.J., Rantala, J., Robson, M., Rodriguez, G.C., Schmutzler, R.K., Selkirk, C.G.H., Shah, P.D., Simard, J., Singer, C.F., Sokolowska, J., Stoppa-Lyonnet, D., Sutter, C., Tan, Y.Y., Teixeira, M.R., Teo, S.H., Terry, M.B., Thomassen, M., Tischkowitz, M., Toland, A.E., Tucker, K.M., Tung, N., Asperen, C.J. van, Engelen, K. van, Rensburg, E.J. van, Wang-Gohrke, S., Wappenschmidt, B., Weitzel, J.N., Yannoukakos, D., Greene, M.H., Rookus, M.A., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., Goldgar, D.E., Olopade, O.I., Rebbeck, T.R., Huo, D.Z., GEMO Study Collaborators, HEBON, EMBRACE, Clinical Genetics, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Leslie, Goska [0000-0001-5756-6222], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Human Genetics, ARD - Amsterdam Reproduction and Development, Epidemiology and Data Science, Human genetics, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: Oncology, Cancer Research, LOCI, Disease, DISEASE, Body Mass Index, breast cancer risk, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, EPIDEMIOLOGY, skin and connective tissue diseases, 2. Zero hunger, BRCA1 Protein, Articles, Prognosis, INSULIN, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], FAMILY, 030220 oncology & carcinogenesis, OBESITY, BIOLOGICAL PATHWAYS, Female, Risk assessment, Adult, medicine.medical_specialty, Breast Neoplasms, Polymorphism, Single Nucleotide, EMBRACE, GEMO Study Collaborators, BMI, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, BRCA1/2, Internal medicine, Mendelian randomization, medicine, Journal Article, Humans, Genetic Predisposition to Disease, HEBON, BRCA2 Protein, IDENTIFICATION, Proportional hazards model, business.industry, Mendelian Randomization Analysis, medicine.disease, Obesity, Confidence interval, Body Height, Mutation, WEIGHT, business, Body mass index
Abstract: Contains fulltext : 206539.pdf (Publisher’s version ) (Closed access) BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.
Published: 2019

39. Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland

Author: Cybulski, C., Lubiński, J., Wokołorczyk, D., Kuźniak, W., Kashyap, A., Sopik, V., Huzarski, T., Gronwald, J., Byrski, T., Szwiec, M., Jakubowska, A., Górski, B., Dębniak, T., Narod, S. A, and Akbari, M. R
Published: 2015
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40. Recurrent mutations of BRCA1 and BRCA2 in Poland: an update

Author: Szwiec, M., Jakubowska, A., Górski, B., Huzarski, T., Tomiczek-Szwiec, J., Gronwald, J., Dębniak, T., Byrski, T., Kluźniak, W., Wokołorczyk, D., Birkenfeld, B., Akbari, M. R., Narod, S. A., Lubiński, J., and Cybulski, C.
Published: 2015
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41. Clinical characteristics of breast cancer in patients with an NBS1 mutation

Author: Huzarski, T., Cybulski, C., Jakubowska, A., Byrski, T., Gronwald, J., Domagała, P., Szwiec, M., Godlewski, D., Kilar, E., Marczyk, E., Siołek, M., Gorski, B., Wiśniowski, R., Janiszewska, H., Surdyka, D., Sibilski, R., Sun, P., Narod, S. A., Lubiński, J., and The Polish Breast Cancer Consortium
Published: 2013
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42. Survival from breast cancer in women with a BRCA2 mutation by treatment.

Author: Evans D.G., Phillips K.-A., Milne R.L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., Narod S.A., Evans D.G., Phillips K.-A., Milne R.L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., and Narod S.A.
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHOD(S): We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULT(S): The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR=1.23 (95% CI, 0.62-2.45, p=0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR=0.45; 95% CI, 0.28-0.72, p=0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p=0.56). CONCLUSION(S): For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

43. 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, Group, A, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, Van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, NV, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Krüger Kjaer, S, Høgdall, E, Campbell, IG, Lázaro, 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, Group, OS, 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, Group, A, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, Van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, NV, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Krüger Kjaer, S, Høgdall, E, Campbell, IG, Lázaro, 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, Group, OS, 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

44. Survival from breast cancer in women with a BRCA2 mutation by treatment

Author: Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, SA, Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, and Narod, SA
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56). CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

45. Survival from breast cancer in women with a BRCA2 mutation by treatment

Author: Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans, D Gareth, Phillips, Kelly-Anne, Milne, Roger L, Fruscio, Robert, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Huzarski, Tomasz, Hyder, Zerin, Forde, Claire, Metcalfe, Kelly, Senter, Leigha, Weitzel, Jeffrey, Tung, Nadine, Zakalik, Dana, Ekholm, Maria, Sun, Ping, Narod, Steven A, Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans, D Gareth, Phillips, Kelly-Anne, Milne, Roger L, Fruscio, Robert, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Huzarski, Tomasz, Hyder, Zerin, Forde, Claire, Metcalfe, Kelly, Senter, Leigha, Weitzel, Jeffrey, Tung, Nadine, Zakalik, Dana, Ekholm, Maria, Sun, Ping, and Narod, Steven A
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation.METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features.RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR=1.23 (95% CI, 0.62-2.45, p=0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR=0.45; 95% CI, 0.28-0.72, p=0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p=0.56).CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

46. Lynch syndrome mutations shared by the Baltic States and Poland

Author: Dymerska, D., Kurzawski, G., Suchy, J., Roomere, H., Toome, K., Metspalu, A., Janavičius, R., Elsakov, P., Irmejs, A., Berzina, D., Miklaševičs, E., Gardovskis, J., Rebane, E., Kelve, M., Kładny, J., Huzarski, T., Gronwald, J., Dębniak, T., Byrski, T., Stembalska, A., Surdyka, D., Siołek, M., Szwiec, M., Banaszkiewicz, Z., Wiśniowski, R., Kilar, E., Scott, R. J., and Lubiński, J.
Published: 2014
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47. Vitamin D receptor variants and breast cancer risk in the Polish population

Author: Gapska, P., Scott, R. J., Serrano-Fernandez, P., Huzarski, T., Byrski, T., Kładny, J., Gronwald, J., Górski, B., Cybulski, C., Lubinski, J., and Dębniak, T.
Published: 2009
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48. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients

Author: Byrski, T., Huzarski, T., Dent, R., Gronwald, J., Zuziak, D., Cybulski, C., Kladny, J., Gorski, B., Lubinski, J., and Narod, S. A.
Published: 2009
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49. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers

Author: Byrski, T., Gronwald, J., Huzarski, T., Grzybowska, E., Budryk, M., Stawicka, M., Mierzwa, T., Szwiec, M., Wiśniowski, R., Siolek, M., Narod, S. A., Lubinski, J., and the Polish Hereditary Breast Cancer Consortium
Published: 2008
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50. Impact of BRCA1 mutation on survival after early onset breast cancer

Author: Huzarski T, Byrski T, Gronwald J, Górski B, Domagała W, Cybulski C, Sun Ping, Oszurek O, Szwiec M, Gugała K, Stawicka M, Morawiec Z, Mierzwa T, Janiszewska H, Kilar E, Marczyk E, Kozak-Klonowska B, Siołek M, Surdyka D, Wiśniowski R, Posmyk M, Lubiński J, and Narod SA
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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