TY - JOUR
T1 - The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk
AU - Mackintosh, Michelle
AU - Derbyshire, Abigail
AU - McVey, Rhona
AU - Bolton, James
AU - Nickkho-Amiry, Mahshid
AU - Higgins, Catherine L
AU - Kamieniorz, Martyna
AU - Pemberton, Philip W.
AU - Kirmani, Bilal H.
AU - Ahmed, Babur
AU - Syed, Akheel
AU - Ammori, Basil
AU - Renehan, Andrew
AU - Kitchener, Henry
AU - Crosbie, Emma
N1 - Funding Information:
1Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom 2Department of Histopathology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom 3Department of Clinical Biochemistry, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom 4Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom 5Department of Obesity Medicine, Diabetes & Endocrinology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom 6Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom 7Obesity and Cancer Research Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom 8Gynaecological Oncology Research Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Funding Information:
We acknowledge the generous gift of time and samples from the women in our study. We would like to thank Hayley Ammori, Joe Woods, Tina Pritchard, Donna Roberts, Adele Poole and Linsey Nelson for their help with patient recruitment, data acquisition, data management and obtaining regulatory approvals. We are grateful for the invaluable assistance of Gill Hesketh who sadly passed away before our study was completed. This article presents independent research funded by the National Institute for Health Research (NIHR), supported by the NIHR Manchester Biomedical Research Centre and facilitated by the Greater Manchester Local Clinical Research Network. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the study; and decision to submit the study for publication.
Publisher Copyright:
© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/10/5
Y1 - 2019/10/5
N2 - Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery-induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III-IV obesity (body mass index ≥40kg/m2 and ≥50kg/m2, respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months’ follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki-67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy-two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was -32.7% and -62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in ten women (14%): four had EC, six had atypical hyperplasia (AH). Following bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki-67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA-IR) and inflammation (hsCRP, IL-6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down-regulation of PI3K-AKT-mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.
AB - Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery-induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III-IV obesity (body mass index ≥40kg/m2 and ≥50kg/m2, respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months’ follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki-67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy-two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was -32.7% and -62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in ten women (14%): four had EC, six had atypical hyperplasia (AH). Following bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki-67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA-IR) and inflammation (hsCRP, IL-6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down-regulation of PI3K-AKT-mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.
KW - obesity
KW - bariatric surgery
KW - weight loss, endometrial cancer, atypical endometrial hyperplasia
KW - atypical endometrial hyperplasia
KW - endometrial cancer
KW - weight loss
KW - Prospective Studies
KW - Humans
KW - Middle Aged
KW - Endometrium/pathology
KW - Young Adult
KW - Bariatric Surgery/methods
KW - Obesity/blood
KW - Adult
KW - Biomarkers/blood
KW - Female
KW - Aged
KW - Cohort Studies
KW - Endometrial Neoplasms/blood
UR - http://www.scopus.com/inward/record.url?scp=85057007161&partnerID=8YFLogxK
U2 - 10.1002/ijc.31913
DO - 10.1002/ijc.31913
M3 - Article
C2 - 30289975
SN - 0020-7136
VL - 144
SP - 641
EP - 650
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -
