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1. Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium : An individual-participant meta-analysis

Author: Brasky, Theodore M., Hade, Erinn M., Cohn, David E., Newton, Alison M., Petruzella, Stacey, O'Connell, Kelli, Bertrand, Kimberly A., Cook, Linda S., De Vivo, Immaculata, Du, Mengmeng, Freudenheim, Jo L., Friedenreich, Christine M., Goodman, Marc T., Gorzelitz, Jessica, Ibiebele, Torukiri I., Krogh, Vittorio, Liao, Linda M., Lipworth, Loren, Lu, Lingeng, McCann, Susan, O'Mara, Tracy A., Palmer, Julie R., Ponte, Jeanette, Prizment, Anna, Risch, Harvey, Sandin, Sven, Schouten, Leo J., Setiawan, Veronica Wendy, Shu, Xiao-ou, Trabert, Britton, Brandt, Piet A. van den, Webb, Penelope M., Wentzensen, Nicolas, Wilkens, Lynne R., Wolk, Alicja, Yu, Herbert, Neuhouser, Marian L., Brasky, Theodore M., Hade, Erinn M., Cohn, David E., Newton, Alison M., Petruzella, Stacey, O'Connell, Kelli, Bertrand, Kimberly A., Cook, Linda S., De Vivo, Immaculata, Du, Mengmeng, Freudenheim, Jo L., Friedenreich, Christine M., Goodman, Marc T., Gorzelitz, Jessica, Ibiebele, Torukiri I., Krogh, Vittorio, Liao, Linda M., Lipworth, Loren, Lu, Lingeng, McCann, Susan, O'Mara, Tracy A., Palmer, Julie R., Ponte, Jeanette, Prizment, Anna, Risch, Harvey, Sandin, Sven, Schouten, Leo J., Setiawan, Veronica Wendy, Shu, Xiao-ou, Trabert, Britton, Brandt, Piet A. van den, Webb, Penelope M., Wentzensen, Nicolas, Wilkens, Lynne R., Wolk, Alicja, Yu, Herbert, and Neuhouser, Marian L.
Abstract: Background. Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial can-cer risk; particularly among certain subgroups characterized by body mass and tumor pathology. Materials and methods. Data from 12 prospective cohort studies participating in the Epidemiology of Endome-trial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid in-takes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study -specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. Results. Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were as-sociated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not dif-fer by cancer grade. Conclusion. Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly over-weight/obese women.(c) 2022 Elsevier Inc. All rights reserved.
Published: 2023
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2. Lifestyle and personal factors associated with having macroscopic residual disease after ovarian cancer primary cytoreductive surgery

Author: Phung, Minh Tung, Phung, Minh Tung, Webb, Penelope M, DeFazio, Anna, Fereday, Sian, Lee, Alice W, Bowtell, David DL, Fasching, Peter A, Goode, Ellen L, Goodman, Marc T, Karlan, Beth Y, Lester, Jenny, Matsuo, Keitaro, Modugno, Francesmary, Brenton, James D, Van Gorp, Toon, Pharoah, Paul DP, Schildkraut, Joellen M, McLean, Karen, Meza, Rafael, Mukherjee, Bhramar, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Terry, Kathryn L, Hanley, Gillian E, Pike, Malcolm C, Berchuck, Andrew, Ramus, Susan J, Pearce, Celeste Leigh, Consortium, on behalf of the Ovarian Cancer Association, Phung, Minh Tung, Phung, Minh Tung, Webb, Penelope M, DeFazio, Anna, Fereday, Sian, Lee, Alice W, Bowtell, David DL, Fasching, Peter A, Goode, Ellen L, Goodman, Marc T, Karlan, Beth Y, Lester, Jenny, Matsuo, Keitaro, Modugno, Francesmary, Brenton, James D, Van Gorp, Toon, Pharoah, Paul DP, Schildkraut, Joellen M, McLean, Karen, Meza, Rafael, Mukherjee, Bhramar, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Terry, Kathryn L, Hanley, Gillian E, Pike, Malcolm C, Berchuck, Andrew, Ramus, Susan J, Pearce, Celeste Leigh, and Consortium, on behalf of the Ovarian Cancer Association
Abstract: ObjectiveThe presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery.MethodsThis analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS.ResultsMenopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53).ConclusionsThe association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.
Published: 2023

3. Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis

Author: Brasky, Theodore M, Hade, Erinn M, Cohn, David E, Newton, Alison M, Petruzella, Stacey, O'Connell, Kelli, Bertrand, Kimberly A, Cook, Linda S, De Vivo, Immaculata, Du, Mengmeng, Freudenheim, Jo L, Friedenreich, Christine M, Goodman, Marc T, Gorzelitz, Jessica, Ibiebele, Torukiri I, Krogh, Vittorio, Liao, Linda M, Lipworth, Loren, Lu, Lingeng, McCann, Susan, O'Mara, Tracy A, Palmer, Julie R, Ponte, Jeanette, Prizment, Anna, Risch, Harvey, Sandin, Sven, Schouten, Leo J, Setiawan, Veronica Wendy, Shu, Xiao-Ou, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Wentzensen, Nicolas, Wilkens, Lynne R, Wolk, Alicja, Yu, Herbert, Neuhouser, Marian L, Brasky, Theodore M, Hade, Erinn M, Cohn, David E, Newton, Alison M, Petruzella, Stacey, O'Connell, Kelli, Bertrand, Kimberly A, Cook, Linda S, De Vivo, Immaculata, Du, Mengmeng, Freudenheim, Jo L, Friedenreich, Christine M, Goodman, Marc T, Gorzelitz, Jessica, Ibiebele, Torukiri I, Krogh, Vittorio, Liao, Linda M, Lipworth, Loren, Lu, Lingeng, McCann, Susan, O'Mara, Tracy A, Palmer, Julie R, Ponte, Jeanette, Prizment, Anna, Risch, Harvey, Sandin, Sven, Schouten, Leo J, Setiawan, Veronica Wendy, Shu, Xiao-Ou, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Wentzensen, Nicolas, Wilkens, Lynne R, Wolk, Alicja, Yu, Herbert, and Neuhouser, Marian L
Abstract: BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology.MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk.RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade.CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.
Published: 2023

4. Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.

Author: Khoja, Lilah, Khoja, Lilah, Weber, Rachel Palmieri, Australian Ovarian Cancer Study Group, Webb, Penelope M, Jordan, Susan J, Muthukumar, Aruna, Chang-Claude, Jenny, Fortner, Renée T, Jensen, Allan, Kjaer, Susanne K, Risch, Harvey, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Berchuck, Andrew, Schildkraut, Joellen M, Cramer, Daniel, Terry, Kathryn L, Anton-Culver, Hoda, Ziogas, Argyrios, Phung, Minh Tung, Hanley, Gillian E, Wu, Anna H, Mukherjee, Bhramar, McLean, Karen, Cho, Kathleen, Pike, Malcolm C, Pearce, Celeste Leigh, Lee, Alice W, Khoja, Lilah, Khoja, Lilah, Weber, Rachel Palmieri, Australian Ovarian Cancer Study Group, Webb, Penelope M, Jordan, Susan J, Muthukumar, Aruna, Chang-Claude, Jenny, Fortner, Renée T, Jensen, Allan, Kjaer, Susanne K, Risch, Harvey, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Berchuck, Andrew, Schildkraut, Joellen M, Cramer, Daniel, Terry, Kathryn L, Anton-Culver, Hoda, Ziogas, Argyrios, Phung, Minh Tung, Hanley, Gillian E, Wu, Anna H, Mukherjee, Bhramar, McLean, Karen, Cho, Kathleen, Pike, Malcolm C, Pearce, Celeste Leigh, and Lee, Alice W
Abstract: ObjectiveTo evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association.MethodsWe conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs).ResultsOverall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99).ConclusionsThe hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.
Published: 2022

5. High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival.

Author: Brieger, Katharine K, Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, Ovarian Cancer Association Consortium, Brieger, Katharine K, Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, and Ovarian Cancer Association Consortium
Abstract: BackgroundThere is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects.MethodsThis analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data.ResultsThere was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54).ConclusionsA higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival.ImpactGiven that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Published: 2022

6. Reproductive Factors Do Not Influence Survival with Ovarian Cancer.

Author: Phung, Minh Tung, Phung, Minh Tung, Alimujiang, Aliya, Berchuck, Andrew, Anton-Culver, Hoda, Schildkraut, Joellen M, Bandera, Elisa V, Chang-Claude, Jenny, Chase, Anne, Doherty, Jennifer Anne, Grout, Bronwyn, Goodman, Marc T, Hanley, Gillian E, Lee, Alice W, McKinnon Deurloo, Cindy, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Pike, Malcolm C, Richardson, Jean, Risch, Harvey A, Sieh, Weiva, Terry, Kathryn L, Webb, Penelope M, Wentzensen, Nicolas, Wu, Anna H, Pearce, Celeste Leigh, Phung, Minh Tung, Phung, Minh Tung, Alimujiang, Aliya, Berchuck, Andrew, Anton-Culver, Hoda, Schildkraut, Joellen M, Bandera, Elisa V, Chang-Claude, Jenny, Chase, Anne, Doherty, Jennifer Anne, Grout, Bronwyn, Goodman, Marc T, Hanley, Gillian E, Lee, Alice W, McKinnon Deurloo, Cindy, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Pike, Malcolm C, Richardson, Jean, Risch, Harvey A, Sieh, Weiva, Terry, Kathryn L, Webb, Penelope M, Wentzensen, Nicolas, Wu, Anna H, and Pearce, Celeste Leigh
Abstract: BackgroundPrevious studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes.MethodsUsing data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype.ResultsDuring the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype.ConclusionsThis study found no association between reproductive factors and survival after an ovarian cancer diagnosis.ImpactReproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.
Published: 2022

7. Getting the MOST out of follow-up : a randomized controlled trial comparing 3 monthly nurse led follow-up via telehealth, including monitoring CA125 and patient reported outcomes using the MOST (Measure of Ovarian Symptoms and Treatment concerns) with routine clinic based or telehealth follow-up, after completion of first line chemotherapy in patients with epithelial ovarian cancer

Author: Cohen, Paul A, Webb, Penelope M, King, Madeleine, Obermair, Andreas, Gebski, Val, Butow, Phyllis, Morton, Rachael, Lawson, Wanda, Yates, Patsy, Campbell, Rachel, Meniawy, Tarek, McMullen, Michelle, Dean, Andrew, Goh, Jeffrey, McNally, Orla, Mileshkin, Linda, Beale, Philip, Beach, Rhonda, Hill, Jane, Dixon, Cyril, Hegarty, Sue, Codde, Jim, Ives, Angela, Lee, Yeh Chen, Brand, Alison, Mellon, Anne, Bilic, Sanela, Black, Isobel, Jeffares, Stephanie, Friedlander, Michael, Cohen, Paul A, Webb, Penelope M, King, Madeleine, Obermair, Andreas, Gebski, Val, Butow, Phyllis, Morton, Rachael, Lawson, Wanda, Yates, Patsy, Campbell, Rachel, Meniawy, Tarek, McMullen, Michelle, Dean, Andrew, Goh, Jeffrey, McNally, Orla, Mileshkin, Linda, Beale, Philip, Beach, Rhonda, Hill, Jane, Dixon, Cyril, Hegarty, Sue, Codde, Jim, Ives, Angela, Lee, Yeh Chen, Brand, Alison, Mellon, Anne, Bilic, Sanela, Black, Isobel, Jeffares, Stephanie, and Friedlander, Michael
Abstract: BACKGROUND: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. PRIMARY OBJECTIVES: To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. STUDY HYPOTHESIS: We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective. TRIAL DESIGN: Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy. PRIMARY ENDPOINTS: Emotional wellbeing at 12 months. SAMPLE SIZE: 150 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL A
Published: 2022

8. The effect of vitamin D supplementation on risk of keratinocyte cancer : an exploratory analysis of the D-Health randomized controlled trial

Author: Ali, Sitwat, Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Romero, Briony Duarte, Mcleod, Donald S.A., Armstrong, Bruce K., Ebeling, Peter R., English, Dallas R., Hartel, Gunter, Van Der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., Neale, Rachel E., Ali, Sitwat, Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Romero, Briony Duarte, Mcleod, Donald S.A., Armstrong, Bruce K., Ebeling, Peter R., English, Dallas R., Hartel, Gunter, Van Der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Neale, Rachel E.
Abstract: Background: Vitamin D may play a role in prevention of keratinocyte cancer (KC), but observational studies examining the association between serum 25-hydroxy vitamin D concentration and KC are largely uninformative because sun exposure causes both KC and vitamin D production. There is scant evidence from clinical trials of supplementary vitamin D. Objectives: To examine the effect of vitamin D supplementation on the risk of developing KC. Methods: We used data from the D-Health Trial, a randomized placebo-controlled trial of vitamin D supplementation (60 000 international units monthly for 5 years) among Australians aged ≥60 years. KC outcomes were captured through linkage to a national administrative dataset for those who consented (N = 20 334; 95%). We used negative binomial regression to analyse the incidence of KC excisions and the incidence of actinic lesions treated using cryotherapy or serial curettage, and flexible parametric survival models for analysis of time to first KC excision. Results: Randomization to vitamin D supplementation did not reduce the incidence of KC lesions treated by excision [incidence rate ratio (IRR) 1·04; 95% confidence interval (CI) 0·98–1·11], the incidence of actinic lesions treated using other methods (IRR 1·01; 95% CI 0·95–1·08) or time to first histologically confirmed KC excision (hazard ratio 1·02; 95% CI 0·97–1·08). However, in subgroup analysis vitamin D increased the incidence of KC excisions in adults aged ≥ 70 years (IRR 1·13, 95% CI 1·04–1·23; P-value for interaction = 0·01). Conclusions: Vitamin D supplementation did not reduce the incidence of KC or other actinic lesions. What is already known about this topic? Laboratory studies have suggested possible protective effects of vitamin D on skin cancer. Observational studies investigating the association between vitamin D and risk of keratinocyte cancer are largely uninformative as ultraviolet radiation both causes skin cancer and is the primary source of vitamin D. T
Published: 2022

9. Vitamin D supplementation and antibiotic use in older Australian adults - an analysis of data from the D-Health Trial

Author: Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Romero, Briony Duarte, Mcleod, Donald S A, Armstrong, Bruce K., Ebeling, Peter R, English, Dallas R., Hartel, Gunter, Kimlin, Michael G, O’Connell, Rachel L., Van Der Pols, Jolieke C, Venn, Alison J., Webb, Penelope M., Whiteman, David C, Neale, Rachel E., Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Romero, Briony Duarte, Mcleod, Donald S A, Armstrong, Bruce K., Ebeling, Peter R, English, Dallas R., Hartel, Gunter, Kimlin, Michael G, O’Connell, Rachel L., Van Der Pols, Jolieke C, Venn, Alison J., Webb, Penelope M., Whiteman, David C, and Neale, Rachel E.
Abstract: Background: Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection. Methods: The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21,315 Australians aged 60-84 years were randomized to 60,000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions; repeat prescription episodes; and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression. Results: Vitamin D supplementation slightly reduced the number of prescription episodes (IRR 0.98, 95% CI 0.95-1.01), total prescriptions (IRR 0.97, 95% CI 0.93-1.00), and repeat prescription episodes (IRR 0.96, 95% CI 0.93-1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR 0.93, 95% CI 0.87-0.99). Conclusions: Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system.
Published: 2022

10. Methodological considerations in D-health cancer mortality results – Authors' reply

Author: Neale, Rachel E., Romero, Briony Duarte, McLeod, Donald S.A., English, Dallas R., Hartel, Gunter, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., Waterhouse, Mary, Neale, Rachel E., Romero, Briony Duarte, McLeod, Donald S.A., English, Dallas R., Hartel, Gunter, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Waterhouse, Mary
Published: 2022

11. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality

Author: Neale, Rachel E., Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Ebeling, Peter, Hartel, Gunter, Kimlin, Michael, O'Connell, Rachel L., van der Pols, Jolieke, Venn, Alison J., Webb, Penelope M., Whiteman, David C., Waterhouse, Mary, Neale, Rachel E., Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Ebeling, Peter, Hartel, Gunter, Kimlin, Michael, O'Connell, Rachel L., van der Pols, Jolieke, Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Waterhouse, Mary
Abstract: Background: The effect of supplementing unscreened adults with vitamin D3 on mortality is unclear. We aimed to determine whether monthly doses of vitamin D3 influenced mortality in older Australians. Methods: We did a randomised, double-blind, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D3 or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. Findings: Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years [IQR 5·4–6·7]), 1100 deaths were recorded (placebo 538 [5·1%]; vitamin D 562 [5·3%]). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D3
Published: 2022

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
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13. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
Full Text: View/download PDF

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
Full Text: View/download PDF

15. Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia.

Author: Hurwitz, Lauren M, Hurwitz, Lauren M, Townsend, Mary K, Jordan, Susan J, Patel, Alpa V, Teras, Lauren R, Lacey, James V, Doherty, Jennifer A, Harris, Holly R, Goodman, Marc T, Shvetsov, Yurii B, Modugno, Francesmary, Moysich, Kirsten B, Robien, Kim, Prizment, Anna, Schildkraut, Joellen M, Berchuck, Andrew, Fortner, Renée T, Chan, Andrew T, Wentzensen, Nicolas, Hartge, Patricia, Sandler, Dale P, O'Brien, Katie M, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Ramus, Susan J, Pearce, Celeste Leigh, Wu, Anna H, White, Emily, Peters, Ulrike, Webb, Penelope M, Tworoger, Shelley S, Trabert, Britton, Hurwitz, Lauren M, Hurwitz, Lauren M, Townsend, Mary K, Jordan, Susan J, Patel, Alpa V, Teras, Lauren R, Lacey, James V, Doherty, Jennifer A, Harris, Holly R, Goodman, Marc T, Shvetsov, Yurii B, Modugno, Francesmary, Moysich, Kirsten B, Robien, Kim, Prizment, Anna, Schildkraut, Joellen M, Berchuck, Andrew, Fortner, Renée T, Chan, Andrew T, Wentzensen, Nicolas, Hartge, Patricia, Sandler, Dale P, O'Brien, Katie M, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Ramus, Susan J, Pearce, Celeste Leigh, Wu, Anna H, White, Emily, Peters, Ulrike, Webb, Penelope M, Tworoger, Shelley S, and Trabert, Britton
Abstract: PurposeFrequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors.MethodsNine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2).ResultsOverall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90).ConclusionThis study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher
Published: 2022

16. Reproductive Factors Do Not Influence Survival with Ovarian Cancer.

Author: Phung, Minh Tung, Phung, Minh Tung, Alimujiang, Aliya, Berchuck, Andrew, Anton-Culver, Hoda, Schildkraut, Joellen M, Bandera, Elisa V, Chang-Claude, Jenny, Chase, Anne, Doherty, Jennifer Anne, Grout, Bronwyn, Goodman, Marc T, Hanley, Gillian E, Lee, Alice W, McKinnon Deurloo, Cindy, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Pike, Malcolm C, Richardson, Jean, Risch, Harvey A, Sieh, Weiva, Terry, Kathryn L, Webb, Penelope M, Wentzensen, Nicolas, Wu, Anna H, Pearce, Celeste Leigh, Phung, Minh Tung, Phung, Minh Tung, Alimujiang, Aliya, Berchuck, Andrew, Anton-Culver, Hoda, Schildkraut, Joellen M, Bandera, Elisa V, Chang-Claude, Jenny, Chase, Anne, Doherty, Jennifer Anne, Grout, Bronwyn, Goodman, Marc T, Hanley, Gillian E, Lee, Alice W, McKinnon Deurloo, Cindy, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Pike, Malcolm C, Richardson, Jean, Risch, Harvey A, Sieh, Weiva, Terry, Kathryn L, Webb, Penelope M, Wentzensen, Nicolas, Wu, Anna H, and Pearce, Celeste Leigh
Abstract: BackgroundPrevious studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes.MethodsUsing data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype.ResultsDuring the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype.ConclusionsThis study found no association between reproductive factors and survival after an ovarian cancer diagnosis.ImpactReproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.
Published: 2022

17. Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.

Author: Khoja, Lilah, Khoja, Lilah, Weber, Rachel Palmieri, Australian Ovarian Cancer Study Group, Webb, Penelope M, Jordan, Susan J, Muthukumar, Aruna, Chang-Claude, Jenny, Fortner, Renée T, Jensen, Allan, Kjaer, Susanne K, Risch, Harvey, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Berchuck, Andrew, Schildkraut, Joellen M, Cramer, Daniel, Terry, Kathryn L, Anton-Culver, Hoda, Ziogas, Argyrios, Phung, Minh Tung, Hanley, Gillian E, Wu, Anna H, Mukherjee, Bhramar, McLean, Karen, Cho, Kathleen, Pike, Malcolm C, Pearce, Celeste Leigh, Lee, Alice W, Khoja, Lilah, Khoja, Lilah, Weber, Rachel Palmieri, Australian Ovarian Cancer Study Group, Webb, Penelope M, Jordan, Susan J, Muthukumar, Aruna, Chang-Claude, Jenny, Fortner, Renée T, Jensen, Allan, Kjaer, Susanne K, Risch, Harvey, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Berchuck, Andrew, Schildkraut, Joellen M, Cramer, Daniel, Terry, Kathryn L, Anton-Culver, Hoda, Ziogas, Argyrios, Phung, Minh Tung, Hanley, Gillian E, Wu, Anna H, Mukherjee, Bhramar, McLean, Karen, Cho, Kathleen, Pike, Malcolm C, Pearce, Celeste Leigh, and Lee, Alice W
Abstract: ObjectiveTo evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association.MethodsWe conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs).ResultsOverall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99).ConclusionsThe hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.
Published: 2022

18. High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival.

Author: Brieger, Katharine K, Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, Ovarian Cancer Association Consortium, Brieger, Katharine K, Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, and Ovarian Cancer Association Consortium
Abstract: BackgroundThere is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects.MethodsThis analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data.ResultsThere was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54).ConclusionsA higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival.ImpactGiven that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Published: 2022

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

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
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
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20. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
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21. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
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
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22. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
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
Full Text: View/download PDF

23. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K, Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, DeFazio, Anna, Johnatty, Sharon E, Webb, Penelope M, Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M, Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K, Goode, Ellen L, Winham, Stacey J, Matsuo, Keitaro, Karlan, Beth Y, Lester, Jenny, Goodman, Marc T, Thompson, Pamela J, Pejovic, Tanja, Riggan, Marjorie J, Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K, Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, DeFazio, Anna, Johnatty, Sharon E, Webb, Penelope M, Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M, Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K, Goode, Ellen L, Winham, Stacey J, Matsuo, Keitaro, Karlan, Beth Y, Lester, Jenny, Goodman, Marc T, Thompson, Pamela J, Pejovic, Tanja, Riggan, Marjorie J, Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: ObjectiveStudies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC.MethodsWomen with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated.ResultsA total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96-1.01 and 0.98; 95%CI 0.95-1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43-12.73) and OS (HR 1.69, 95%CI 0.56-5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36-5.81) and OS (HR 6.62, 95%CI 2.45-17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85).ConclusionAdvanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS.Highlights1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although
Published: 2022

24. Effects of risk factors for ovarian cancer in women with and without endometriosis.

Author: Phung, Minh Tung, Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Jensen, Allan, Kjaer, Susanne K, Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, Lee, Alice W, Phung, Minh Tung, Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Jensen, Allan, Kjaer, Susanne K, Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, and Lee, Alice W
Abstract: ObjectiveTo evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis.DesignPooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium.SettingPopulation-based.Patient(s)We included 8,500 women with ovarian cancer, 13,592 control women.Intervention(s)Ten well-established ovarian cancer risk factors.Main outcome measure(s)Risk of ovarian cancer for women with and without endometriosis.Result(s)Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively).Conclusion(s)The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormo
Published: 2022

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

Author: DeVries, Amber A, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, OPAL Study Group, AOCS Group, Håkansson, Niclas, Hildebrandt, Michelle AT, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul DP, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, OPAL Study Group, AOCS Group, Håkansson, Niclas, Hildebrandt, Michelle AT, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul DP, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
Abstract: BackgroundKnown 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.MethodsSingle 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.ResultsWe 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.ConclusionsCNVs 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

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

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
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
Full Text: View/download PDF

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, select and shrink for summary statistics (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

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

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
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
Full Text: View/download PDF

29. Coffee consumption and risk of endometrial cancer: a pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Author: Crous-Bou, Marta, Du, Mengmeng, Gunter, Marc J, Setiawan, Veronica W, Schouten, Leo J, Shu, Xiao-Ou, Wentzensen, Nicolas, Bertrand, Kimberly A, Cook, Linda S, Friedenreich, Christine M, Gapstur, Susan M, Goodman, Marc T, Ibiebele, Torukiri I, La Vecchia, Carlo, Levi, Fabio, Liao, Linda M, Negri, Eva, McCann, Susan E, O'Connell, Kelly, Palmer, Julie R, Patel, Alpa V, Ponte, Jeanette, Reynolds, Peggy, Sacerdote, Carlotta, Sinha, Rashmi, Spurdle, Amanda B, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Petruzella, Stacey, Olson, Sara H, De Vivo, Immaculata, Epidemiology of Endometrial Cancer Consortium (E2C2), Crous-Bou, Marta, Du, Mengmeng, Gunter, Marc J, Setiawan, Veronica W, Schouten, Leo J, Shu, Xiao-Ou, Wentzensen, Nicolas, Bertrand, Kimberly A, Cook, Linda S, Friedenreich, Christine M, Gapstur, Susan M, Goodman, Marc T, Ibiebele, Torukiri I, La Vecchia, Carlo, Levi, Fabio, Liao, Linda M, Negri, Eva, McCann, Susan E, O'Connell, Kelly, Palmer, Julie R, Patel, Alpa V, Ponte, Jeanette, Reynolds, Peggy, Sacerdote, Carlotta, Sinha, Rashmi, Spurdle, Amanda B, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Petruzella, Stacey, Olson, Sara H, De Vivo, Immaculata, and Epidemiology of Endometrial Cancer Consortium (E2C2)
Abstract: BACKGROUND: Epidemiological studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating levels of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund concluded that consumption of coffee probably protects against EC.OBJECTIVE: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors of EC.PATIENTS AND METHODS: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 endometrial cancer cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate odds ratios (OR) and their corresponding 95% confidence intervals (CI). All models were adjusted for potential confounders including age, race, body mass index, smoking status, diabetes status, study design and study site.RESULTS: Coffee drinkers had a lower risk of EC compared to non-coffee drinkers (multi-adjusted OR = 0.87, 95% CI = 0.79,0.95). There was a dose-response relationship between higher coffee consumption and lower risk of EC: compared to non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3 and more than 4 cups/day were 0.90 (95% CI = 0.82,1.00), 0.86 (95% CI = 0.78,0.95), and 0.76 (95% CI = 0.66,0.87), respectively (p for trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with body mass index (BMI) over 25 kg/m2.CONCLUSION: The results of the largest analysis to date pooling individual-level d
Published: 2022

30. Effects of risk factors for ovarian cancer in women with and without endometriosis

Author: Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B., Jensen, Allan, Kjaer, Susanne K., Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, Lee, Alice W, Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B., Jensen, Allan, Kjaer, Susanne K., Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, and Lee, Alice W
Abstract: Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. Setting: Population-based. Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women. Intervention(s): Ten well-established ovarian cancer risk factors. Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis. Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25–<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00–1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91–1.05) when compared with BMI 18.5–<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94–1.57) to women without (OR = 1.13; 95% CI, 1.04–1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04–1.84 vs. OR = 1.12; 95% CI, 1.01–1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09–3.24 vs. OR = 1.42; 95% CI, 1.14–1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differe
Published: 2022

31. Effects of risk factors for ovarian cancer in women with and without endometriosis

Author: Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B., Jensen, Allan, Kjaer, Susanne K., Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, Lee, Alice W, Phung, Minh Tung, Muthukumar, Aruna, Trabert, Britton, Webb, Penelope M, Jordan, Susan J, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda J, Risch, Harvey A, Doherty, Jennifer Anne, Harris, Holly R, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B., Jensen, Allan, Kjaer, Susanne K., Anton-Culver, Hoda, Ziogas, Argyrios, Berchuck, Andrew, Khoja, Lilah, Wu, Anna H, Pike, Malcolm C, Pearce, Celeste Leigh, and Lee, Alice W
Abstract: Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. Setting: Population-based. Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women. Intervention(s): Ten well-established ovarian cancer risk factors. Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis. Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25–<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00–1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91–1.05) when compared with BMI 18.5–<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94–1.57) to women without (OR = 1.13; 95% CI, 1.04–1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04–1.84 vs. OR = 1.12; 95% CI, 1.01–1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09–3.24 vs. OR = 1.42; 95% CI, 1.14–1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differe
Published: 2022

32. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre-and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. Results: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96–1.01 and 0.98; 95%CI 0.95–1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43–12.73) and OS (HR 1.69, 95%CI 0.56–5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36–5.81) and OS (HR 6.62, 95%CI 2.45–17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). Conclusion: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. Highlights: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analy
Published: 2022

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmana, Judith, Bandera, Elisa, V, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia, V, Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dork, Thilo, du Bois, Andreas, Durst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, ReneeT, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Group, Opal Study, Group, AOCS, Hahnen, Eric, Haiman, Christopher A., Hakansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Hogdall, Estrid, Hogdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., KimMatsuno, Rayna, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo, I, Olson, Sara H., Olsson, Hakan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamarina, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., BethTerry, Mary, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Nieuwenhuysen, ElsVan, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
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34. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre-and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. Results: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96–1.01 and 0.98; 95%CI 0.95–1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43–12.73) and OS (HR 1.69, 95%CI 0.56–5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36–5.81) and OS (HR 6.62, 95%CI 2.45–17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). Conclusion: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. Highlights: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analy
Published: 2022

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

Author: Song, Honglin, Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, Pharoah, Paul, Song, Honglin, Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, and Pharoah, Paul
Abstract: PurposeThe 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.MethodsWe 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.ResultsThe 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.ConclusionsWe 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

36. Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.

Author: Lee, Alice W, Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Australian Ovarian Cancer Study Group, Ramus, Susan J, Menon, Usha, Gentry-Maharaj, Aleksandra, Ziogas, Argyrios, Anton-Culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, McGuire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-Claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul DP, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, Pearce, Celeste Leigh, Lee, Alice W, Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Australian Ovarian Cancer Study Group, Ramus, Susan J, Menon, Usha, Gentry-Maharaj, Aleksandra, Ziogas, Argyrios, Anton-Culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, McGuire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-Claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul DP, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, and Pearce, Celeste Leigh
Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.
Published: 2021

37. Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium

Author: Jordan, Susan J., Jordan, Susan J., Na, Renhua, Weiderpass, Elisabete, Adami, Hans-Olov, Anderson, Kristin E., van den Brandt, Piet A., Brinton, Louise A., Chen, Chu, Cook, Linda S., Doherty, Jennifer A., Du, Mengmeng, Friedenreich, Christine M., Gierach, Gretchen L., Goodman, Marc T., Krogh, Vittorio, Levi, Fabio, Lu, Lingeng, Miller, Anthony B., McCann, Susan E., Moysich, Kirsten B., Negri, Eva, Olson, Sara H., Petruzella, Stacey, Palmer, Julie R., Parazzini, Fabio, Pike, Malcolm C., Prizment, Anna E., Rebbeck, Timothy R., Reynolds, Peggy, Ricceri, Fulvio, Risch, Harvey A., Rohan, Thomas E., Sacerdote, Carlotta, Schouten, Leo J., Serraino, Diego, Setiawan, Veronica W., Shu, Xiao-Ou, Sponholtz, Todd R., Spurdle, Amanda B., Stolzenberg-Solomon, Rachael Z., Trabert, Britton, Wentzensen, Nicolas, Wilkens, Lynne R., Wise, Lauren A., Yu, Herbert, La Vecchia, Carlo, De Vivo, Immaculata, Xu, Wanghong, Zeleniuch-Jacquotte, Anne, Webb, Penelope M., Jordan, Susan J., Jordan, Susan J., Na, Renhua, Weiderpass, Elisabete, Adami, Hans-Olov, Anderson, Kristin E., van den Brandt, Piet A., Brinton, Louise A., Chen, Chu, Cook, Linda S., Doherty, Jennifer A., Du, Mengmeng, Friedenreich, Christine M., Gierach, Gretchen L., Goodman, Marc T., Krogh, Vittorio, Levi, Fabio, Lu, Lingeng, Miller, Anthony B., McCann, Susan E., Moysich, Kirsten B., Negri, Eva, Olson, Sara H., Petruzella, Stacey, Palmer, Julie R., Parazzini, Fabio, Pike, Malcolm C., Prizment, Anna E., Rebbeck, Timothy R., Reynolds, Peggy, Ricceri, Fulvio, Risch, Harvey A., Rohan, Thomas E., Sacerdote, Carlotta, Schouten, Leo J., Serraino, Diego, Setiawan, Veronica W., Shu, Xiao-Ou, Sponholtz, Todd R., Spurdle, Amanda B., Stolzenberg-Solomon, Rachael Z., Trabert, Britton, Wentzensen, Nicolas, Wilkens, Lynne R., Wise, Lauren A., Yu, Herbert, La Vecchia, Carlo, De Vivo, Immaculata, Xu, Wanghong, Zeleniuch-Jacquotte, Anne, and Webb, Penelope M.
Abstract: A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
Published: 2021

38. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author: Kho, Pik Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H.T., Cook, Linda S., Crous-Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, Dörk, Thilo, Dowdy, Sean C., Dunning, Alison M., Dürst, Matthias, Easton, Douglas F., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Friedenreich, Christine M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goode, Ellen L., Gorman, Maggie, Haiman, Christopher A., Hall, Per, Hankinson, Susan E., Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A., Holliday, Elizabeth G., Hunter, David J., Jones, Angela M., Kraft, Peter, Krakstad, Camilla, Lambrechts, Diether, Le Marchand, Loic, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M., Martin, Lynn, McEvoy, Mark, Milne, Roger L., Mints, Miriam, Nassir, Rami, Otton, Geoffrey, Palles, Claire, Pooler, Loreall, Proietto, Tony, Rebbeck, Timothy R., Renner, Stefan P., Risch, Harvey A., Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E., Schumacher, Fredrick, Scott, Rodney J., Setiawan, V. Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao Ou, Southey, Melissa C., Tham, Emma, Tomlinson, Ian, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P., Van Den Berg, David, Wang, Zhaoming, Wentzensen, Nicolas, Xia, Lucy, Xiang, Yong Bing, Yang, Hannah P., Yu, Herbert, Zheng, Wei, Webb, Penelope M., Thompson, Deborah J., Spurdle, Amanda B., Glubb, Dylan M., O'Mara, Tracy A., Kho, Pik Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H.T., Cook, Linda S., Crous-Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, Dörk, Thilo, Dowdy, Sean C., Dunning, Alison M., Dürst, Matthias, Easton, Douglas F., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Friedenreich, Christine M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goode, Ellen L., Gorman, Maggie, Haiman, Christopher A., Hall, Per, Hankinson, Susan E., Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A., Holliday, Elizabeth G., Hunter, David J., Jones, Angela M., Kraft, Peter, Krakstad, Camilla, Lambrechts, Diether, Le Marchand, Loic, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M., Martin, Lynn, McEvoy, Mark, Milne, Roger L., Mints, Miriam, Nassir, Rami, Otton, Geoffrey, Palles, Claire, Pooler, Loreall, Proietto, Tony, Rebbeck, Timothy R., Renner, Stefan P., Risch, Harvey A., Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E., Schumacher, Fredrick, Scott, Rodney J., Setiawan, V. Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao Ou, Southey, Melissa C., Tham, Emma, Tomlinson, Ian, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P., Van Den Berg, David, Wang, Zhaoming, Wentzensen, Nicolas, Xia, Lucy, Xiang, Yong Bing, Yang, Hannah P., Yu, Herbert, Zheng, Wei, Webb, Penelope M., Thompson, Deborah J., Spurdle, Amanda B., Glubb, Dylan M., and O'Mara, Tracy A.
Abstract: Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10−8) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
Published: 2021

39. Vitamin D supplementation and risk of falling : outcomes from the randomized, placebo-controlled D-Health Trial

Author: Waterhouse, Mary, Sanguineti, Emma, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Ebeling, Peter R., Hartel, Gunter, Kimlin, Michael G., O'Connell, Rachel L., Pham, Hai, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., Neale, Rachel E., Waterhouse, Mary, Sanguineti, Emma, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Ebeling, Peter R., Hartel, Gunter, Kimlin, Michael G., O'Connell, Rachel L., Pham, Hai, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Neale, Rachel E.
Abstract: Background: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls. Methods: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60–84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. Results: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4
Published: 2021

40. Predicting deseasonalised serum 25 hydroxy vitamin D concentrations in the D-Health Trial: An analysis using boosted regression trees

Author: Waterhouse, Mary, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Clarke, Michael W., Ebeling, Peter, Hartel, Gunter, Kimlin, Michael, O'Connell, Rachel L., Pham, Hai, Rodney Harris, Rachael M., van der Pols, Jolieke, Venn, Alison J., Webb, Penelope M., Whiteman, David C., Neale, Rachel E, Waterhouse, Mary, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., English, Dallas R., Armstrong, Bruce K., Clarke, Michael W., Ebeling, Peter, Hartel, Gunter, Kimlin, Michael, O'Connell, Rachel L., Pham, Hai, Rodney Harris, Rachael M., van der Pols, Jolieke, Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Neale, Rachel E
Abstract: Background: The D-Health Trial aims to determine whether monthly high-dose vitamin D supplementation can reduce the mortality rate and prevent cancer. We did not have adequate statistical power for subgroup analyses, so could not justify the high cost of collecting blood samples at baseline. To enable future exploratory analyses stratified by baseline vitamin D status, we developed models to predict baseline serum 25 hydroxy vitamin D [25(OH)D] concentration. Methods: We used data and serum 25(OH)D concentrations from participants who gave a blood sample during the trial for compliance monitoring and were randomised to placebo. Data were partitioned into training (80%) and validation (20%) datasets. Deseasonalised serum 25(OH)D concentrations were dichotomised using cut-points of 50, 60 and 75 nmol/L. We fitted boosted regression tree models, based on 13 predictors, and evaluated model performance using the validation data. Results: The training and validation datasets had 1788 (10.5% <50 nmol/L, 23.1% <60 nmol, 48.8 <75 nmol/L) and 447 (11.9% <50 nmol/L, 25.7% <60 nmol/L, and 49.2% <75 nmol/L) samples, respectively. Ambient UV radiation and total intake of vitamin D were the strongest predictors of ‘low’ serum 25(OH)D concentration. The area under the receiver operating characteristic curves were 0.71, 0.70, and 0.66 for cut-points of <50, <60 and <75 nmol/L respectively. Conclusions: We exploited compliance monitoring data to develop models to predict serum 25(OH)D concentration for D-Health participants at baseline. This approach may prove useful in other trial settings where there is an obstacle to exhaustive data collection.
Published: 2021

41. Dietitian encounters after treatment for ovarian cancer

Author: Johnston, Elizabeth, Ibiebele, Torukiri I., van der Pols, Jolieke, Webb, Penelope M., other, and, Johnston, Elizabeth, Ibiebele, Torukiri I., van der Pols, Jolieke, Webb, Penelope M., and other, and
Abstract: Background: After ovarian cancer treatment, women report health issues that may be amenable to change with dietary support. The present study investigated how many women encounter a dietitian post-treatment and the factors associated with dietitian service use. Methods: We used data from a cohort of women with invasive epithelial ovarian cancer to identify socio-economic, clinical and personal factors associated with dietitian encounter after treatment completion. Data were collected at regular intervals using validated questionnaires up to 4 years post-treatment completion. Logistic regression (LR) and generalised linear mixed models (GLMM) were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) to assess factors associated with dietitian encounter at any time-point post-treatment (LR), as well as in the 3 months prior to a follow-up questionnaire (GLMM) to assess time-varying factors. Results: Of 819 women, 97 (12%) reported seeing a dietitian post-treatment. Factors associated with dietitian encounter were being overweight (ORLR = 1.7, CI = 1.1–2.8), having poorer self-rated health (ORLR = 2.5, CI = 1.2–5.2; ORGLMM = 2.3, CI = 1.2–4.4) or poorer diet quality (ORLR = 0.5, CI = 0.2–1.0) pre-diagnosis, treatment within the public health system (ORGLMM = 1.8, CI = 1.2–2.7), previous support from dietetic (ORLR = 3.1, CI = 1.8–5.4; ORGLMM = 2.8, CI = 1.8–4.2) or other allied health services (ORLR = 2.0, CI = 1.2–3.2; ORGLMM = 3.7, CI = 2.4–5.5), and having progressive disease at follow-up (ORGLMM = 2.2, CI = 1.4–3.3). Most women (86%) with ≥ 3 moderate-to-severe nutrition impact symptoms did not report a dietitian encounter post-treatment. Conclusions: Few women encounter a dietitian post-treatment for ovarian cancer, including those with multiple nutrition impact symptoms. Further work is needed to engage those likely to benefit
Published: 2021

42. The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial

Author: Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., Armstrong, Bruce K., Ebeling, Peter R., English, Dallas R., Hartel, Gunter, Kimlin, Michael G., Martineau, Adrian R., O'Connell, Rachel, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., Neale, Rachel E., Pham, Hai, Waterhouse, Mary, Baxter, Catherine, Duarte Romero, Briony, McLeod, Donald S.A., Armstrong, Bruce K., Ebeling, Peter R., English, Dallas R., Hartel, Gunter, Kimlin, Michael G., Martineau, Adrian R., O'Connell, Rachel, van der Pols, Jolieke C., Venn, Alison J., Webb, Penelope M., Whiteman, David C., and Neale, Rachel E.
Abstract: Background: Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections. Methods: We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regressio
Published: 2021

43. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author: Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, other, and, Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, and other, and
Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
Published: 2021

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

Author: Song, Honglin, Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, Pharoah, Paul, Song, Honglin, Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, and Pharoah, Paul
Abstract: PurposeThe 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.MethodsWe 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.ResultsThe 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.ConclusionsWe 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

45. Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.

Author: Lee, Alice W, Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Australian Ovarian Cancer Study Group, Ramus, Susan J, Menon, Usha, Gentry-Maharaj, Aleksandra, Ziogas, Argyrios, Anton-Culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, McGuire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-Claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul DP, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, Pearce, Celeste Leigh, Lee, Alice W, Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Australian Ovarian Cancer Study Group, Ramus, Susan J, Menon, Usha, Gentry-Maharaj, Aleksandra, Ziogas, Argyrios, Anton-Culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, McGuire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-Claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul DP, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, and Pearce, Celeste Leigh
Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.
Published: 2021

46. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Author: Quinn, Michael CJ, Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, Chenevix-Trench, Georgia, AGO Study Group, OPAL Study Group, for Australian Ovarian Cancer Study Group, Quinn, Michael CJ, Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, Chenevix-Trench, Georgia, AGO Study Group, OPAL Study Group, and for Australian Ovarian Cancer Study Group
Abstract: BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.
Published: 2021

47. Evaluating the role of alcohol consumption in breast and ovarian cancer susceptibility using population-based cohort studies and two-sample Mendelian randomization analyses

Author: Ong, Jue Sheng, Derks, Eske M., Eriksson, Mikael, An, Jiyuan, Hwang, Liang Dar, Easton, Douglas F., Pharoah, Paul P., Berchuck, Andrew, Kelemen, Linda E., Matsuo, Keitaro, Chenevix-Trench, Georgia, Hall, Per, Bojesen, Stig E., Webb, Penelope M., MacGregor, Stuart, Ong, Jue Sheng, Derks, Eske M., Eriksson, Mikael, An, Jiyuan, Hwang, Liang Dar, Easton, Douglas F., Pharoah, Paul P., Berchuck, Andrew, Kelemen, Linda E., Matsuo, Keitaro, Chenevix-Trench, Georgia, Hall, Per, Bojesen, Stig E., Webb, Penelope M., and MacGregor, Stuart
Abstract: Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.
Published: 2021

48. Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium

Author: Jordan, Susan J., Na, Renhua, Weiderpass, Elisabete, Adami, Hans-Olov, Anderson, Kristin E., van den Brandt, Piet A., Brinton, Louise A., Chen, Chu, Cook, Linda S., Doherty, Jennifer A., Du, Mengmeng, Friedenreich, Christine M., Gierach, Gretchen L., Goodman, Marc T., Krogh, Vittorio, Levi, Fabio, Lu, Lingeng, Miller, Anthony B., McCann, Susan E., Moysich, Kirsten B., Negri, Eva, Olson, Sara H., Petruzella, Stacey, Palmer, Julie R., Parazzini, Fabio, Pike, Malcolm C., Prizment, Anna E., Rebbeck, Timothy R., Reynolds, Peggy, Ricceri, Fulvio, Risch, Harvey A., Rohan, Thomas E., Sacerdote, Carlotta, Schouten, Leo J., Serraino, Diego, Setiawan, Veronica W., Shu, Xiao-Ou, Sponholtz, Todd R., Spurdle, Amanda B., Stolzenberg-Solomon, Rachael Z., Trabert, Britton, Wentzensen, Nicolas, Wilkens, Lynne R., Wise, Lauren A., Yu, Herbert, La Vecchia, Carlo, De Vivo, Immaculata, Xu, Wanghong, Zeleniuch-Jacquotte, Anne, Webb, Penelope M., Jordan, Susan J., Na, Renhua, Weiderpass, Elisabete, Adami, Hans-Olov, Anderson, Kristin E., van den Brandt, Piet A., Brinton, Louise A., Chen, Chu, Cook, Linda S., Doherty, Jennifer A., Du, Mengmeng, Friedenreich, Christine M., Gierach, Gretchen L., Goodman, Marc T., Krogh, Vittorio, Levi, Fabio, Lu, Lingeng, Miller, Anthony B., McCann, Susan E., Moysich, Kirsten B., Negri, Eva, Olson, Sara H., Petruzella, Stacey, Palmer, Julie R., Parazzini, Fabio, Pike, Malcolm C., Prizment, Anna E., Rebbeck, Timothy R., Reynolds, Peggy, Ricceri, Fulvio, Risch, Harvey A., Rohan, Thomas E., Sacerdote, Carlotta, Schouten, Leo J., Serraino, Diego, Setiawan, Veronica W., Shu, Xiao-Ou, Sponholtz, Todd R., Spurdle, Amanda B., Stolzenberg-Solomon, Rachael Z., Trabert, Britton, Wentzensen, Nicolas, Wilkens, Lynne R., Wise, Lauren A., Yu, Herbert, La Vecchia, Carlo, De Vivo, Immaculata, Xu, Wanghong, Zeleniuch-Jacquotte, Anne, and Webb, Penelope M.
Abstract: A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
Published: 2021

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

Author: Song, Honglin, Dicks, Ed M., Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D., Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, Van Oudenhove, Elke, Doherty, Jen, Harris, Holly R., Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V., Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y., Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G., Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J., Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B., Levine, Douglas A., Schildkraut, Joellen M., Riggan, Marjorie J., Berchuck, Andrew, Webb, Penelope M., Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L., Wu, Anna H., De Fazio, Anna, Kennedy, Catherine J., Goode, Ellen, Ramus, Susan, Gayther, Simon, Pharoah, Paul, Song, Honglin, Dicks, Ed M., Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D., Traficante, Nadia, Group, Aocs, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, Van Oudenhove, Elke, Doherty, Jen, Harris, Holly R., Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V., Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y., Lester, Jenny, Jensen, Allan, Krüger Kjaer, Susanne, Høgdall, Estrid, Campbell, Ian G., Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J., Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B., Levine, Douglas A., Schildkraut, Joellen M., Riggan, Marjorie J., Berchuck, Andrew, Webb, Penelope M., Group, Opal Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L., Wu, Anna H., De Fazio, Anna, Kennedy, Catherine J., Goode, Ellen, Ramus, Susan, Gayther, Simon, and Pharoah, Paul
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

50. Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Author: Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Ramus, Susan J, Menon, Usha, Gentry-maharaj, Aleksandra, Ziogas, Argyrios, Anton-culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, Mcguire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul D P, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, Pearce, Celeste Leigh, Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Ramus, Susan J, Menon, Usha, Gentry-maharaj, Aleksandra, Ziogas, Argyrios, Anton-culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, Mcguire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul D P, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, and Pearce, Celeste Leigh
Published: 2021

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