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1. Supplementary information from Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer

Author

Håvard E. Danielsen, Jone Trovik, Helga B. Salvesen, Knut Liestøl, Fritz Albregtsen, Line Bjørge, Henrica M.J. Werner, Frederic Amant, Margaret S. Lode, Jostein Tjugum, Jan A. Rokne, Klaus Oddenes, Runar Eraker, Hans K. Haugland, Anne C. Staff, Solveig Tingulstad, Janusz Marcickiewicz, Manohar Pradhan, Wanja Kildal, Marna L. Kjæreng, John Arne Nesheim, Rolf Anders Syvertsen, Birgitte Nielsen, Tormund S. Njølstad, and Tarjei S. Hveem

Abstract

Supplementary information describing the Nucleotyping method in more detail, including the training and validation results for the calculated Nucleotyping features.

Published
2023

2. Data from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.

Published
2023

3. Supplemental Table 1. Details of cases and controls included in the endometrial cancer analyses from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Excel file detailing case-control populations

Published
2023

4. Supplemental Table 2. Average BMIs in the ANECS, SEARCH and iCOGS endometrial cancer datasets. from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Excel file detailing average BMI per study population

Published
2023

5. Supplementary Table 3: Association of 77 body mass index (BMI) SNPs with endometrial cancer risk and BMI in the endometrial cancer dataset from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Excel file detailing single BMI SNP associations with EC risk and BMI

Published
2023

6. Data from Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer

Author

Håvard E. Danielsen, Jone Trovik, Helga B. Salvesen, Knut Liestøl, Fritz Albregtsen, Line Bjørge, Henrica M.J. Werner, Frederic Amant, Margaret S. Lode, Jostein Tjugum, Jan A. Rokne, Klaus Oddenes, Runar Eraker, Hans K. Haugland, Anne C. Staff, Solveig Tingulstad, Janusz Marcickiewicz, Manohar Pradhan, Wanja Kildal, Marna L. Kjæreng, John Arne Nesheim, Rolf Anders Syvertsen, Birgitte Nielsen, Tormund S. Njølstad, and Tarjei S. Hveem

Abstract

Background: Most endometrial carcinoma patients are diagnosed at an early stage with a good prognosis. However, a relatively low fraction with lethal disease constitutes a substantial number of patients due to the high incidence rate. Preoperative identification of patients with high risk and low risk for poor outcome is necessary to tailor treatment. Nucleotyping refers to characterization of cell nuclei by image cytometry, including the assessment of chromatin structure by nuclear texture analysis. This method is a strong prognostic marker in many cancers but has not been evaluated in preoperative curettage specimens from endometrial carcinoma.Methods: The prognostic impact of changes in chromatin structure quantified with Nucleotyping was evaluated in preoperative curettage specimens from 791 endometrial carcinoma patients prospectively included in the MoMaTEC multicenter trial.Results: Nucleotyping was an independent prognostic marker of disease-specific survival in preoperative curettage specimens among patients with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I–II disease (HR=2.9; 95% CI, 1.2–6.5; P = 0.013) and significantly associated with age, FIGO stage, histologic type, histologic grade, myometrial infiltration, lymph node status, curettage histology type, and DNA ploidy.Conclusions: Nucleotyping in preoperative curettage specimens is an independent prognostic marker for disease-specific survival, with potential to supplement existing parameters for risk stratification to tailor treatment.Impact: This is the first study to evaluate the prognostic impact of Nucleotyping in curettage specimens from endometrial carcinoma and shows that this may be a clinically useful prognostic marker in endometrial cancer. External validation is warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 61–67. ©2016 AACR.

Published
2023

7. Supplementary Table 4. Association of 47 waist-hip ratio (WHR) SNPs with endometrial cancer risk from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Excel file detailing single WHR SNP associations with EC risk

Published
2023

8. Supplementary Text for: Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author

Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter

Abstract

Supplementary Text for manuscript.

Published
2023

9. Late-week surgical treatment of endometrial cancer is associated with worse long-term outcome: Results from a prospective, multicenter study.

Author

Tormund S Njølstad, Henrica M Werner, Janusz Marcickiewicz, Solveig Tingulstad, Anne C Staff, Klaus Oddenes, Line Bjørge, Marie E Engh, Kathrine Woie, Jostein Tjugum, Margaret S Lode, Frederic Amant, Helga B Salvesen, and Jone Trovik

Subjects
Medicine, Science
Abstract

Surgery is the cornerstone in primary endometrial cancer treatment, and with curative intent it constitutes total hysterectomy and bilateral salpingo-oopherectomy. In addition, lymphadenectomy is performed in selected patients dependent on a preoperative risk assessment. Recent reports from the surgical approach to esophageal cancer reveal worse outcome when esophagectomy is performed later in the week. On this basis, we set out to explore weekday of surgery in relation to long-term outcome in 1302 endometrial cancer patients prospectively included in the MoMaTEC multicenter study. Day of surgery was dichotomized as early-week (Monday-Tuesday) or late-week (Wednesday-Friday), and evaluated as a discrete variable. Adjusted for patient age, Body Mass Index (BMI), FIGO stage, and histology, surgery performed later in the week was associated with 50.9% increased risk of all-cause death (p = 0.029). Among high-stage patients (FIGO stage III and IV), 5-year disease-specific survival proportions were 53.0% for early-week operated vs. 40.2% for late-week operated (p = 0.005 for difference). In multivariate survival analysis of high-stage patients, late-week surgery correlated with an increased risk of disease-specific death by 88.7% and all-cause death by 76.4% (p0.05). In conclusion, endometrial cancer surgery conducted late-week is associated with worse long-term outcome. Our findings are most evident among patients with higher FIGO stages, and patients who underwent more extensive surgical procedure (lymphadenectomy). With support from other studies, our results suggest that high-risk patients may benefit from surgery earlier in the week.

Published
2017
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