Table 1:
Summary of endometrial cancer risk factors, genetics, and biomarkers
| Domain | Factor | Estimated Relative Riska |
Heterogeneity of risk | Comments | Highest level of evidence |
Refs |
|---|---|---|---|---|---|---|
| Metabolic factors | Obesity | 2.0–5.0 | Association stronger for type I than II cancers | Each 5 kg/m2 increase in body mass index (BMI) is associated with a 62% increased risk | Cohort study | (22, 83) |
| Diabetes | 2.0 | No heterogeneity observed | Uncertain extent to which relations are confounded by obesity | Meta-analysis of cohort studies | (26, 83) | |
| Hypertension | 1.1–1.3 | Not examined | Association between hypertension and endometrial cancer was weaker, but still significant, among studies with adjustment for BMI | Meta-analysis of case-control and cohort studies | (27) | |
| Metabolic syndrome | 1.4–2.0 | No heterogeneity observed | Adjustment for overweight/obesity does not eliminate increased risks associated with metabolic syndrome factors | Meta-analysis of case-control and cohort studies | (29, 114) | |
| Polycystic ovary syndrome | 2.8 | Not examined | Uncertain extent to which relations are confounded by obesity | Meta-analysis of case-control studies | (28) | |
| Reproductive factors | Nulliparity | 3.0 | Association restricted to type I cancers | Further reductions for multi-parous women | Meta-analysis of case-control and cohort studies | (31, 115) |
| Infertility | 1.8 | No heterogeneity observed | Even after adjusting for nulliparity, infertile women had increased risk | Pooled analysis of case-control and cohort studies | (32) | |
| Early age at menarche | 1.5–2.0 | No heterogeneity observed | 4% reduction in risk per 2 years delay in menarcheal age | Meta-analysis of cohort studies | (33, 86) | |
| Late age at natural menopause | 1.5–2.2 | No heterogeneity observed | Pronounced risks among nonusers of menopausal hormones | Cohort studies | (86, 115, 116) | |
| Breastfeeding | 0.9 | No heterogeneity observed | Greatest reductions for long-term breastfeeding | Pooled analysis of case-control and cohort studies | (36) | |
| Contraceptives | Combination oral contraceptives | 0.3–0.5 | No heterogeneity observed | Risk reduction persists for > 30 years | Pooled analysis of case-control and cohort studies | (83, 86) |
| Intrauterine device use | 0.5–0.8 | Association stronger for type I than II cancers | More studies needed on the effects of progestin-releasing devices | Pooled analysis of case-control and cohort studies | (37, 38) | |
| Menopausal hormone therapy | Menopausal estrogens | 10.0–20.0 | Not examined | Highest risks for long-term and high dose users of unopposed estrogens | Cohort study | (39) |
| Menopausal estrogen plus progestins | 0.7 | Association stronger for type I than II cancers | Risk reduction is greatest for obese women | Randomized trial | (39, 42, 43) | |
| Tamoxifen use | High cumulative doses of tamoxifen | 2.2 | Non-endometrioid histology subtypes appear to be especially affected by tamoxifen | Endometrial cancer risks highest shortly after exposure | Randomized trial | (44, 117) |
| Lifestyle factors | Cigarette smoking | 0.5 | No heterogeneity observed | Effects of cigarette smoking are particularly strong among postmenopausal women and menopausal hormone users | Meta-analysis of case-control and cohort studies | (46, 83) |
| Moderate-to-vigorous physical activity | 0.8 | No heterogeneity observed | Inverse relation with physical activity restricted to overweight or obese women | Meta-analysis of case-control and cohort studies | (48, 86, 118) | |
| Family history | Family history | 1.8 | No heterogeneity observed | Association is independent of Lynch syndrome status | Meta-analysis of case-control and cohort studies | (73, 119) |
| High penetrance gene mutations | MLH1 | 18–54% lifetime risk | Not examined | (74–76) | ||
| MSH2 | 21–49% lifetime risk | Not examined | (74–76) | |||
| MSH6 | 16–61% lifetime risk | Not examined | (75, 76) | |||
| PMS2 | 12% lifetime risk | Not examined | (77) | |||
| EPCAM | 12% lifetime risk | Not examined | (78) | |||
| Low and moderate penetrance genes | 1.1–1.4 | Some SNP associations differ according to histology | (120) | |||
| Serum biomarkers | Estradiol and other endogenous estrogens | 2.0–6.2 | Some support for stronger relations with type I than II cancers | Associations persist after adjustment for body mass and show slightly stronger relations for type I than II cancers | (91) | |
| Insulin | Significant mean difference between endometrial cancer cases and controls: 33.94 | Not examined | This meta-analysis did not detect an association among studies restricted to postmenopausal women, possibly due to small numbers | (94) | ||
| C-peptide | Significant mean difference between endometrial cancer cases and controls: 0.14 | Not examined | A lack of information on fasting time since the last meal may have led to misclassification of C-peptide levels | (94) | ||
| Androgen | Postmenopausal: 1.7 Premenopausal: 0.9 |
Similar associations observed when restricted to women with type I | Higher circulating levels of androgens are associated with endometrial cancer among postmenopausal women | (88–90, 92, 93) | ||
| Inflammatory markers | SERPINE1: 2.4 VEGF-A: 2.6 Anti-inflammatory cytokines (IL13, IL21): 0.5–0.6 Pro-inflammatory cytokines (CCL3, IL1B, IL23): 0.5–0.6 |
No heterogeneity observed although the number of women with type II was small | Endometrial cancer risk was most pronounced among obese women with the highest inflammation score | (97) | ||
| Adiponectin | 0.5 | Not examined | Inverse associations were strongest among postmenopausal women, nulliparous women, and non-hormone users | (98) | ||
| Leptin | 2.2 | Not examined | Associations were strongest among non-hormone users, diabetic women, and in prospective studies | (98) |