The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk

Michelle Mackintosh, Abigail Derbyshire, Rhona McVey, James Bolton, Mahshid Nickkho-Amiry, Catherine L Higgins, Martyna Kamieniorz, Philip W. Pemberton, Bilal H. Kirmani, Babur Ahmed, Akheel Syed, Basil Ammori, Andrew Renehan, Henry Kitchener, Emma Crosbie

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)641-650
Number of pages10
JournalInternational Journal of Cancer
Volume144
Issue number3
Early online date5 Oct 2018
DOIs
Publication statusPublished - 5 Oct 2019

Keywords

  • obesity
  • bariatric surgery
  • weight loss, endometrial cancer, atypical endometrial hyperplasia
  • atypical endometrial hyperplasia
  • endometrial cancer
  • weight loss
  • Prospective Studies
  • Humans
  • Middle Aged
  • Endometrium/pathology
  • Young Adult
  • Bariatric Surgery/methods
  • Obesity/blood
  • Adult
  • Biomarkers/blood
  • Female
  • Aged
  • Cohort Studies
  • Endometrial Neoplasms/blood

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