Abstract
Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002–2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)2) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.
Keywords: DNA mismatch repair, endometrial neoplasms, microsatellite instability, risk factors
Endometrial cancer is the most common gynecological cancer among women in Western countries. In Canada, 5,300 new endometrial cancer cases and 900 associated deaths are estimated to have occurred in 2012 (1). Obesity is a well-established risk factor for endometrial cancer (2–5), and previous studies have shown that recent obesity is associated with increased risk of endometrial cancer (6–9). However, the associations between anthropometric measures over adult life and endometrial cancer risk have been inconsistent. Although the majority of studies evaluating anthropometric measures over the course of adult life and endometrial cancer risk have reported a positive association (6–8, 10–13), studies that controlled for body mass index (BMI) at baseline or contemporary weight have not (14–16).
Microsatellite instability is a molecular phenotype characterized by alterations in the length of short (1–5 base pairs) tandem repeats of DNA in tumor cells compared with normal cells (i.e., cells with germ-line DNA) of the same patient (17). Microsatellite instability is an underlying feature of hereditary nonpolyposis colorectal cancer (HNPCC), a syndrome that includes colon and endometrial cancer, but microsatellite instability also occurs in approximately 30% of endometrial cancers that are not associated with any inherited syndromes—that is, sporadic endometrial cancer (18–21). Only 2 previous studies have reported on the associations between BMI and microsatellite-stable (MSS) and microsatellite-instable (MSI) endometrial cancer. Both studies included endometrial cancer cases only and found a higher median or mean BMI among MSS endometrial cancer cases than among MSI cases (22, 23). Recently, Win et al. (24) showed that BMI in early adulthood (at age 20 years) increased the risk of endometrial cancer in noncarriers of mismatch repair (MMR) gene mutations, but not in carriers, suggesting differential risk of endometrial cancer associated with BMI based on MMR status. To our knowledge, no study to date has comprehensively examined the relationship between anthropometric factors and the risk of endometrial cancer stratified by microsatellite status.
Our goal in this population-based case-control analysis was to evaluate the risk of endometrial cancer overall and by the microsatellite status of tumors and histological subtypes associated with recent and adult-life anthropometric measures.
MATERIALS AND METHODS
Study population
Details on the study have been published elsewhere (25). Briefly, study subjects were female residents of Alberta, Canada, aged 30–79 years, without a previous diagnosis of any cancer except nonmelanoma skin cancer, who participated in a province-wide case-control study between September 2002 and February 2006. Cases, women with histologically confirmed incident endometrial cancer, were identified from the population-based Alberta Cancer Registry through rapid case ascertainment. Controls, women with no history of hysterectomy, were identified using random-digit dialing and were frequency-matched to cases by 5-year age group. Participation rates were 67.9% and 52.2% for cases and controls, respectively. All study participants provided signed, informed consent, and the study protocol was approved by the ethics review boards of the Alberta Cancer Board and the University of Calgary.
The present analysis included 542 cases and 1,032 controls with satisfactory interviews. For the microsatellite instability analysis, 45 cases were excluded for the following reasons: no hysterectomy performed (n = 10), refused tissue testing (n = 4), no available pathological slides/tissue (n = 3), no observable cancer at slide review (n = 12), and no matching blood (n = 16). This left 497 potential cases for microsatellite instability testing. Among these cases, the assay failed for 6 cases, and for 11 others there was missing information on some aspect of microsatellite instability testing. We further excluded 13 cases and 2 controls who belonged to HNPCC families based on the Amsterdam II criteria (26, 27); this left 467 cases (337 MSS and 130 MSI) and 1,030 controls in the final microsatellite instability analysis. For the histological subtype analysis, 18 cases with other types of cancer were excluded, leaving 524 cases (458 type I and 66 type II) and 1,032 controls.
Data collection
Exposure and covariate information was obtained through in-person interviews that ascertained lifestyle factors, health behaviors, and medical history (25). Data included directly measured weight and waist and hip circumferences using standardized protocols, as well as self-reported usual adult height and weight in each decade from age 20 years to age 60 years. All exposure information was ascertained for the time period before diagnosis for cases and an analogous reference date for controls (25).
Determination of microsatellite status
Genomic DNA was extracted from buffy coat and from two 40-μm sections of archival paraffin-embedded tumor tissue blocks. We obtained all of the tissue blocks for each case, and after histological review by the study pathologist (A.M.M.), we selected a single representative tumor block with 70% or more cancer cells that had sufficient tissue for sectioning. When necessary, nontumor tissue was removed using a hematoxylin-and-eosin stain of the block for guidance. Extraction was performed using a Qiagen kit (Qiagen Inc., Toronto, Ontario, Canada) according to the manufacturer's instructions, and DNA was quantified using absorbance spectrophotometry. Each tumor was evaluated with 5 microsatellite markers (Bat25, Bat26, D5S346, D2S123, and D17S250) recommended by the US National Cancer Institute (26). DNA was amplified using fluorescently labeled primers of the markers according to the following touch-down polymerase chain reaction (PCR) protocol: step 1—an initial denaturation at 94°C for 10 minutes; step 2—8 cycles at 94°C for 30 seconds, 56°C–60°C (with a 1°C decrease after each cycle) for 30 seconds, and 72°C for 1 minute; step 3—35 cycles at 94°C for 30 seconds, 48°C–52°C for 30 seconds, and 72°C for 1 minute; and step 4—a final extension at 72°C for 10 minutes. Each PCR reaction contained 50–200 ng of genomic DNA in a total reaction volume of 25 µL. PCR reactions were carried out separately for each of the markers or by multiplexing reactions for Bat25 and D17S250 or Bat26 and D2S123.
To increase efficiency, all PCR reactions for each sample were pooled together before running them in capillaries on an ABI 377 Sequencer (Applied Biosystems Ltd., Mississauga, Ontario, Canada). Microsatellite analysis was conducted using Genemapper 3.7 software (Applied Biosystems Ltd.). A mismatch error was defined as additional alleles in tumor DNA compared with germ-line DNA. Tumors with 2 or more mismatch errors were classified as MSI, and tumors with 1 or none were classified as MSS (26). Analyses for samples with ambiguous results were repeated to obtain a clear result the second time, and analyses for 10% of the samples were rerun for reproducibility. We observed 100% reproducibility when we scored the microsatellite status of patients as MSS or MSI.
Blood or normal tissue DNA has been used as germ-line DNA in previous endometrial cancer studies to determine the microsatellite status of tumors (20, 28), but it is not known whether or not they provide the same results. To address this question, we determined the MSI status of 14 randomly selected endometrial tumors using both blood and normal tissue (fallopian tube or ovary) as germ-line DNA. With 14 cases, the power to detect excellent agreement (29) was greater than 90% (30). We observed 100% agreement (κ = 1.00) for microsatellite status between germ-line DNA from blood and germ-line DNA from normal tissue. Blood DNA, which was readily available, was used as the germ-line DNA in this study.
Histological subtype
The study pathologist (A.M.M.) classified tumors as type I (n = 458; endometrioid, adenocarcinoma tubular, papillary adenocarcinoma, adenocarcinoma with squamous metaplasia, mucinous adenocarcinoma, and adenocarcinoma, not otherwise specified) or type II (n = 66; clear cell, serous, papillary serous, adenosquamous, and mixed-cell adenocarcinoma) on the basis of histopathological reports. Eighteen cases with other types of cancer were excluded from this classification. Type 1 tumors are generally low-grade cancers that are hormone-responsive with a favorable prognosis, while the rarer type II tumors are typically higher-grade and more aggressive, with a worse prognosis (31).
Statistical analysis
Weight gain since age 20 years was calculated as the difference between weight at the reference date and weight at age 20 years, and BMI was calculated as weight in kilograms divided by the square of height in meters. To generate categorical variables for the anthropometric measures, we divided the study participants into quartiles based on the distributions in controls, except for BMI. BMI was categorized as <25, 25–<30, or ≥30. Anthropometric characteristics on the reference date as well as change in the characteristics over adult life were examined.
We examined the association between each anthropometric characteristic and risk of endometrial cancer overall and by microsatellite tumor status or histological subtype. Associations between anthropometric characteristics and risk of overall endometrial cancer or histological subtypes were estimated with odds ratios and 95% confidence intervals using unconditional logistic regression, while associations for subtypes based on microsatellite status were estimated using polytomous logistic regression, and the P value for heterogeneity of odds ratios was determined using a Wald test. Linear trends in risks were examined by modeling categorical anthropometric characteristics as ordinal variables and calculating the Wald statistic (32).
The following potential confounders identified a priori were evaluated in univariate analyses: age at menarche (years; continuous), age at menopause (years; continuous), menopausal status/hormone use (peri- or postmenopausal/never use, peri- or postmenopausal/estrogen only use, peri- or postmenopausal/any use of estrogen plus progesterone, or peri- or postmenopausal/other menopausal hormone use or premenopausal hormone use), parity/age at first pregnancy (nulliparous, 1–2/≤25 years, 1–2/>25 years, >2/≤25 years, or >2/>25 years), use of hormonal contraception (including both oral contraceptives and shots/implants) (ever or never), history of smoking (ever or never), hypertension (ever or never), and education (high school diploma, nonuniversity certificate, or university degree). For the microsatellite analysis, factors that were significant (P < 0.05) in the univariate analyses were included in the multivariable analysis. For the analysis of histological subtype, factors that were significant (P < 0.25) in univariate analyses and changed the effect estimate by at least 15% were included in the multivariable analysis. The final statistical models included the study design variables (reference age (continuous) and residential type (rural or urban)), age at menarche, menopausal status/hormone use, parity/age at first pregnancy, and hypertension for the microsatellite analysis and age at the reference date and hypertension for the histological subtype analysis.
All statistical tests were 2-sided with α = 0.05, and all analyses were conducted with Stata, version 10 (StataCorp LP, College Station, Texas). A 2-sided P value of 0.05 or less was considered statistically significant.
RESULTS
The mean ages of controls (58.1 years) and cases (overall: 59.0 years; MSS: 58.7 years; MSI: 59.5 years) were similar, as expected because of the frequency-matching on age (Table 1). Cases were more likely than controls to have an earlier age at menarche, to have a later age at menopause, to be nulliparous, to have not used hormonal contraception, and to have been diagnosed with hypertension (Table 1).
Table 1.
Characteristics of Endometrial Cancer Cases and Controls, Alberta, Canada, 2002–2006a
| Characteristic | Controls (n = 1,030) |
All Cases (n = 467) |
MSS Cases (n = 337) |
MSI Cases (n = 130) |
||||
|---|---|---|---|---|---|---|---|---|
| Mean or No. | % | Mean or No. | % | Mean or No. | % | Mean or No. | % | |
| Mean reference age, years (SD) | 58.1 (10.1) | 59.0 (9.3) | 58.7 (9.3) | 59.5 (9.2) | ||||
| Educational level | ||||||||
| High school diploma or less | 291 | 28.3 | 154 | 33.0 | 100 | 29.7 | 54 | 41.5 |
| Nonuniversity certificate | 490 | 47.6 | 212 | 45.4 | 158 | 46.9 | 54 | 41.5 |
| University degree | 248 | 24.1 | 101 | 21.6 | 79 | 23.4 | 22 | 16.9 |
| Residence type | ||||||||
| Urban | 665 | 64.6 | 315 | 67.5 | 227 | 67.4 | 88 | 67.7 |
| Rural | 365 | 35.4 | 152 | 32.5 | 110 | 32.6 | 42 | 32.3 |
| Age at menarche, years | ||||||||
| ≤12 | 517 | 50.2 | 274 | 58.7 | 206 | 61.1 | 68 | 52.3 |
| >12 | 513 | 49.8 | 193 | 41.3 | 131 | 38.9 | 62 | 47.7 |
| Age at menopause, years | ||||||||
| ≥50 | 442 | 59.7 | 233 | 64.7 | 171 | 66.3 | 62 | 60.8 |
| <50 | 299 | 40.3 | 127 | 35.3 | 87 | 33.7 | 40 | 39.2 |
| Menopausal status/ hormone use | ||||||||
| Peri- or postmenopausal/ never use | 509 | 49.8 | 258 | 55.5 | 183 | 54.6 | 75 | 57.7 |
| Peri- or postmenopausal/ use of estrogen only | 25 | 2.4 | 17 | 3.7 | 15 | 4.5 | 2 | 1.5 |
| Peri- or postmenopausal/ any use of estrogen plus progesterone | 334 | 32.7 | 119 | 25.6 | 82 | 24.5 | 37 | 28.5 |
| Peri- or postmenopausal/ other use | 29 | 2.8 | 23 | 5.0 | 19 | 5.7 | 4 | 3.1 |
| Premenopausal | 126 | 12.3 | 48 | 10.3 | 36 | 10.8 | 12 | 9.2 |
| Parity/age at first pregnancy, years | ||||||||
| Nulliparous | 106 | 10.3 | 83 | 17.8 | 62 | 18.4 | 21 | 16.2 |
| 1–2/≤25 | 201 | 19.5 | 124 | 26.6 | 88 | 26.1 | 36 | 27.7 |
| 1–2/>25 | 226 | 21.9 | 69 | 14.8 | 50 | 14.8 | 19 | 14.6 |
| >2/≤25 | 401 | 38.9 | 161 | 34.5 | 110 | 32.6 | 51 | 39.2 |
| >2/>25 | 96 | 9.3 | 30 | 6.4 | 27 | 8.0 | 3 | 2.3 |
| Use of hormonal contraceptives | ||||||||
| Never use (<6 months) | 300 | 29.1 | 182 | 39.0 | 126 | 37.4 | 56 | 43.1 |
| Ever use (≥6 months) | 720 | 69.9 | 278 | 59.5 | 206 | 61.1 | 72 | 55.4 |
| Smoking | ||||||||
| Never smoking (<100 cigarettes in lifetime) | 515 | 50.0 | 238 | 51.0 | 176 | 52.2 | 62 | 47.7 |
| Ever smoking | 515 | 50.0 | 229 | 49.0 | 161 | 47.8 | 68 | 52.3 |
| Hypertension | ||||||||
| Yes | 270 | 26.2 | 196 | 42.0 | 144 | 42.7 | 52 | 40.0 |
| No | 760 | 73.8 | 271 | 58.0 | 193 | 57.3 | 78 | 60.0 |
Abbreviations: MSI, microsatellite-instable; MSS, microsatellite-stable; SD, standard deviation.
a Numbers may not add up to totals because of missing data.
We found that 27.8% (130/467) of our sporadic endometrial cancers were of the MSI subtype. The risks for overall, MSS, and MSI endometrial cancer increased with an increase in all of the anthropometric characteristics at the reference date (all P-trend values < 0.001) (Table 2). The magnitude of the associations was suggestively stronger for MSI cancer, and significant heterogeneity was observed for BMI. Women with a BMI of ≥30 had a risk of MSI tumors (odds ratio (OR) = 4.96, 95% confidence interval (CI): 2.76, 8.91) that was more than twice the risk of MSS tumors (OR = 2.33, 95% CI: 1.66, 3.28) (P-heterogeneity = 0.02) (Table 2). Women with a BMI of 25–<30 had an increased risk of MSI tumors (OR = 2.09, 95% CI: 1.13, 3.86) but not MSS tumors (OR = 1.07, 95% CI: 0.74, 1.53) (P-heterogeneity = 0.05) (Table 2). The increased risk with greater current weight was completely attenuated after adjustment for waist circumference (Appendix Table 1). For BMI, the increased risks observed for overall cancer (P-trend = 0.86) and MSS cancer (P-trend = 0.38) were completely attenuated after adjusting for waist circumference, but the risk for MSI cancer persisted with borderline significance (P-trend = 0.05) (Appendix Table 1). While this may represent overadjustment, there was still a stronger risk (approximately 2-fold) for MSI cancers compared with MSS cancers for both women with a BMI of 25–<30 (P-heterogeneity = 0.03) and women with a BMI of ≥30 (P-heterogeneity = 0.01) (Appendix Table 1).
Table 2.
Associations Between Anthropometric Factors at the Reference Date and Overall, MSS, and MSI Endometrial Cancer, Alberta, Canada, 2002–2006a
| Variable | No. of Controls (n = 1,030) | All Cases (n = 467) vs. Controls |
MSS Cases (n = 337) vs. Controls |
MSI Cases (n = 130) vs. Controls |
P-hetb | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | ORc | 95% CI | No. | ORc | 95% CI | No. | ORc | 95% CI | |||
| Current weight, kg | |||||||||||
| ≤63.2 | 257 | 73 | 1.00 | 57 | 1.00 | 16 | 1.00 | ||||
| >63.2–71.5 | 259 | 62 | 0.88 | 0.59, 1.30 | 43 | 0.78 | 0.50, 1.22 | 19 | 1.21 | 0.61, 2.43 | 0.27 |
| >71.5–81.7 | 256 | 102 | 1.42 | 0.99, 2.04 | 74 | 1.31 | 0.87, 1.95 | 28 | 1.81 | 0.95, 3.47 | 0.37 |
| >81.7 | 257 | 230 | 3.10 | 2.21, 4.32 | 163 | 2.74 | 1.89, 3.97 | 67 | 4.35 | 2.40, 7.88 | 0.17 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
| Body mass indexd | |||||||||||
| <25 | 335 | 87 | 1.00 | 71 | 1.00 | 16 | 1.00 | ||||
| 25–<30 | 378 | 124 | 1.26 | 0.91, 1.73 | 87 | 1.07 | 0.74, 1.53 | 37 | 2.09 | 1.13, 3.86 | 0.05 |
| ≥30 | 316 | 256 | 2.81 | 2.06, 3.84 | 179 | 2.33 | 1.66, 3.28 | 77 | 4.96 | 2.76, 8.91 | 0.02 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
| Waist circumference, cm | |||||||||||
| ≤76.5 | 257 | 51 | 1.00 | 39 | 1.00 | 12 | 1.00 | ||||
| >76.5–84.8 | 255 | 72 | 1.47 | 0.97, 2.21 | 53 | 1.41 | 0.89, 2.23 | 19 | 1.65 | 0.78, 3.48 | 0.71 |
| >84.8–96.0 | 262 | 120 | 2.34 | 1.59, 3.43 | 90 | 2.27 | 1.48, 3.49 | 30 | 2.53 | 1.25, 5.10 | 0.79 |
| >96.0 | 251 | 220 | 4.21 | 2.90, 6.10 | 153 | 3.74 | 2.47, 5.67 | 67 | 5.74 | 2.97, 11.11 | 0.25 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
| Hip circumference, cm | |||||||||||
| ≤99.0 | 269 | 74 | 1.00 | 54 | 1.00 | 20 | 1.00 | ||||
| >99.0–104.7 | 243 | 71 | 1.09 | 0.75, 1.59 | 54 | 1.14 | 0.75, 1.75 | 17 | 0.96 | 0.49, 1.88 | 0.64 |
| >104.7–112.7 | 256 | 102 | 1.48 | 1.03, 2.11 | 77 | 1.53 | 1.02, 2.28 | 25 | 1.35 | 0.72, 2.51 | 0.72 |
| >112.7 | 256 | 216 | 2.87 | 2.05, 4.00 | 150 | 2.68 | 1.84, 3.90 | 66 | 3.40 | 1.96, 5.89 | 0.45 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
| Waist:hip ratio, per 0.1 unit | |||||||||||
| ≤0.76 | 247 | 60 | 1.00 | 46 | 1.00 | 14 | 1.00 | ||||
| >0.76–0.81 | 267 | 108 | 1.66 | 1.15, 2.40 | 79 | 1.59 | 1.05, 2.40 | 29 | 1.89 | 0.97, 3.68 | 0.65 |
| >0.81–0.86 | 240 | 113 | 1.86 | 1.28, 2.69 | 80 | 1.71 | 1.13, 2.59 | 33 | 2.32 | 1.20, 4.49 | 0.41 |
| >0.86 | 270 | 182 | 2.57 | 1.80, 3.67 | 130 | 2.38 | 1.60, 3.54 | 52 | 3.18 | 1.70, 5.97 | 0.41 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
Abbreviations: CI, confidence interval; MSI, microsatellite-instable; MSS, microsatellite-stable; OR, odds ratio.
a Numbers may not add up to totals because of missing data (1 control was missing data on current weight and body mass index; 5 controls and 4 cases were missing data on waist circumference, hip circumference, and waist:hip ratio).
b P value for heterogeneity between odds ratios for MSS and MSI, both compared with controls.
c Odds ratios were adjusted for reference age (years; continuous), residence type (rural or urban), age at menarche (≤12 years or >12 years), menopausal status/hormone use (peri- or postmenopausal/never use, peri- or postmenopausal/use of estrogen only, peri- or postmenopausal/any use of estrogen plus progesterone, or peri- or postmenopausal/other menopausal hormone use or premenopausal hormone use), parity/age at first pregnancy (nulliparous, 1–2/≤25 years, 1–2/>25 years, >2/≤25 years, or >2/>25 years), and hypertension (ever or never).
d Weight (kg)/height (m)2.
Similar to anthropometric variables at the reference date, we observed increasing risks for overall, MSS, and MSI endometrial cancers with increasing adult-life obesity or size measures (all P-trend values < 0.005), although for weight at age 20 years the trend for MSI tumors was of borderline significance (P-trend = 0.07) (Table 3). However, the positive associations for weight at age 20 years and weight gain since age 20 years were completely attenuated after adjustment for current weight (Appendix Table 2). In contrast, the positive associations for weight gain since age 20 years persisted after adjustment for weight at age 20 years (Appendix Table 2). For increasing maximum weight gain in adult life, the positive associations for overall (P-trend = 0.025) and MSI (P-trend = 0.013) cancer persisted, while that for MSS cancer was completely attenuated, after adjustment for current weight (data not shown).
Table 3.
Association Between Anthropometric Factors Over the Lifetime and Overall, MSS, and MSI Endometrial Cancer, Alberta, Canada, 2002–2006a
| Variable | No. of Controls (n = 1,030) | All Cases (n = 467) vs. Controls |
MSS Cases (n = 337) vs. Controls |
MSI Cases (n = 130) vs. Controls |
P-hetb | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | ORc | 95% CI | No. | ORc | 95% CI | No. | ORc | 95% CI | |||
| Weight at age 20 years, kg | |||||||||||
| ≤49.9 | 282 | 99 | 1.00 | 69 | 1.00 | 30 | 1.00 | ||||
| >49.9–54.4 | 162 | 66 | 1.28 | 0.88, 1.87 | 53 | 1.50 | 0.99, 2.28 | 13 | 0.80 | 0.40, 1.59 | 0.10 |
| >54.4–59.0 | 331 | 150 | 1.35 | 0.99, 1.84 | 102 | 1.33 | 0.93, 1.90 | 48 | 1.41 | 0.86, 2.29 | 0.85 |
| >59.0 | 255 | 152 | 1.71 | 1.24, 2.34 | 113 | 1.81 | 1.27, 2.59 | 39 | 1.46 | 0.87, 2.43 | 0.45 |
| P-trend | 0.005 | <0.005 | 0.07 | ||||||||
| Weight gain since age 20 years, kg | |||||||||||
| ≤8.7 | 257 | 71 | 1.00 | 52 | 1.00 | 19 | 1.00 | ||||
| >8.7–16.7 | 257 | 79 | 1.11 | 0.76, 1.62 | 61 | 1.18 | 0.78, 1.80 | 18 | 0.92 | 0.47, 1.80 | 0.50 |
| >16.7–25.9 | 259 | 108 | 1.41 | 0.99, 2.03 | 80 | 1.43 | 0.95, 2.14 | 28 | 1.38 | 0.74, 2.57 | 0.93 |
| >25.9 | 256 | 209 | 2.76 | 1.97, 3.87 | 144 | 2.56 | 1.75, 3.75 | 65 | 3.32 | 1.90, 5.81 | 0.41 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
| Difference between maximum and minimum weights over the course of adult life, kg | |||||||||||
| ≤10.0 | 272 | 68 | 1.00 | 53 | 1.00 | 15 | 1.00 | ||||
| >10.0–16.8 | 245 | 69 | 1.09 | 0.74, 1.61 | 56 | 1.13 | 0.74, 1.73 | 13 | 0.94 | 0.43, 2.02 | 0.66 |
| >16.8–24.9 | 230 | 83 | 1.35 | 0.92, 1.97 | 53 | 1.10 | 0.71, 1.69 | 30 | 2.25 | 1.17, 4.33 | 0.06 |
| >24.9 | 283 | 247 | 3.14 | 2.25, 4.39 | 175 | 2.80 | 1.93, 4.05 | 72 | 4.37 | 2.39, 7.98 | 0.18 |
| P-trend | <0.001 | <0.001 | <0.001 | ||||||||
Abbreviations: CI, confidence interval; MSI, microsatellite-instable; MSS, microsatellite-stable; OR, odds ratio.
a Numbers may not add up to totals because of missing data (1 control was missing data on weight gain since age 20 years).
b P value for heterogeneity between odds ratios for MSS and MSI, both compared with controls.
c Odds ratios were adjusted for reference age (years; continuous), residence type (rural or urban), age at menarche (≤12 years or >12 years), menopausal status/hormone use (peri- or postmenopausal/never use, peri- or postmenopausal/use of estrogen only, peri- or postmenopausal/any use of estrogen plus progesterone, or peri- or postmenopausal/other menopausal hormone use or premenopausal hormone use), parity/age at first pregnancy (nulliparous, 1–2/≤25 years, 1–2/>25 years, >2/≤25 years, or >2/>25 years), and hypertension (ever or never).
The risk of type I endometrial cancer increased with increases in all of the anthropometric characteristics (Table 4). In contrast, type II endometrial cancer was not strongly associated with any anthropometric characteristic. In this small number of cases (n = 66), there was only the suggestion of an increased risk of type II endometrial cancer with increasing waist circumference and increasing weight gain in adult life (Table 4).
Table 4.
Odds Ratios for Endometrial Cancer According to Anthropometric Factors and Histological Subtype (Type I or Type IIa), Alberta, Canada, 2002–2006
| Risk Factor | Type I (n = 1,490b) |
Type II (n = 1,098c) |
||||||
|---|---|---|---|---|---|---|---|---|
| Age-Adjusted |
Multivariable-Adjustedd |
Age-Adjusted |
Multivariable-Adjustedd |
|||||
| OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| Current weight, kg | 1.04 | 1.03, 1.04 | 1.04 | 1.03, 1.04 | 1.01 | 1.00, 1.03 | 1.01 | 0.99, 1.02 |
| Waist circumference, cm | 1.04 | 1.03, 1.05 | 1.04 | 1.03, 1.05 | 1.02 | 1.00, 1.04 | 1.01 | 1.00, 1.03 |
| Hip circumference, cm | 1.05 | 1.04, 1.05 | 1.04 | 1.03, 1.05 | 1.02 | 1.00, 1.04 | 1.01 | 0.99, 1.03 |
| Body mass index,e per unit | 1.11 | 1.09, 1.13 | 1.10 | 1.08, 1.12 | 1.04 | 1.00, 1.08 | 1.02 | 0.98, 1.07 |
| Waist:hip ratio, per 0.1 unit | 1.62 | 1.41, 1.87 | 1.52 | 1.32, 1.76 | 1.38 | 1.01, 1.88 | 1.26 | 0.91, 1.75 |
| Weight at age 20 years, kg | 1.03 | 1.02, 1.04 | 1.03 | 1.02, 1.04 | 1.00 | 0.97, 1.03 | 1.00 | 0.97, 1.02 |
| Weight gain since age 20 years, kg | 1.04 | 1.03, 1.04 | 1.04 | 1.03, 1.04 | 1.01 | 1.00, 1.03 | 1.01 | 0.99, 1.03 |
| Difference between maximum and minimum weights over the course of adult life, kg | 1.04 | 1.03, 1.05 | 1.04 | 1.03, 1.05 | 1.03 | 1.01, 1.04 | 1.02 | 1.00, 1.04 |
a Eighteen cases with other types of endometrial cancer were excluded.
b 458 cases and 1,032 controls.
c 66 cases and 1,032 controls.
d Adjusted for age at the reference date and hypertension.
e Weight (kg)/height (m)2.
DISCUSSION
In this study, we evaluated comprehensively the association between recent and adult-life anthropometric characteristics and the risk of endometrial cancer, overall and stratified by microsatellite tumor status and histological subtype. Consistent with previous studies (6–8, 10, 12, 13), we observed an increased risk of overall endometrial cancer with recent and adult-life anthropometric characteristics. A novel finding of our study was that the risk of MSI tumors among women with a high BMI or a greater weight change during adulthood was twice that of MSS tumors. Type I endometrial cancer risk increased with an increase in all of the anthropometric characteristics, but there was only a suggestion of an increased risk for type II endometrial cancer with increasing waist circumference and increasing weight gain in adult life. Our finding of an increased risk of type I endometrial cancer with high BMI, which is conventionally considered to arise in hyperestrogenic states, is consistent with the findings of a recent meta-analysis (33). Both increased (34, 35) and decreased (36) risks of type II endometrial cancer with BMI have been reported. However, the observed lack of association between anthropometric variables and type II endometrial cancer in our study may be attributable to insufficient statistical power. Therefore, future larger studies are warranted to investigate these associations further.
Obesity is the most well-established endometrial cancer risk factor to date, and obesity during early adult life and weight changes over the course of adult life have been of particular interest. Numerous studies (6–8, 10–13, 37) have shown that the risk of endometrial cancer increases with obesity in early adult life, but studies that have controlled for recent obesity (6, 7, 38) have shown that recent obesity may be more important than obesity in early adult life. In our study, the association for weight at age 20 years was attenuated for overall endometrial cancer after controlling for current weight or waist circumference. In contrast, increasing maximum weight gain over the course of adult life was a strong risk factor for overall endometrial cancer, even after adjustment for current weight and waist circumference in our analysis. This variable of weight gain likely captures large changes in weight, such as those characteristic of weight cycling, lending support to the notion that weight cycling is a risk factor for endometrial cancer independently of recent anthropometric measures (15). Although the mechanism underlying the association between weight cycling and cancer risk is not well understood, insulin-like growth factor 1 could potentially play a role in weight cycling similar to that suggested for body size in early life (39).
Our finding that women with a high BMI have an increased risk of MSI endometrial tumors as compared with MSS endometrial tumors is intriguing but is not consistent with the findings from 2 previous endometrial cancer case series (22, 23). Both case series found a higher median or mean BMI among MSS endometrial cancer cases compared with MSI cases, and the authors suggested that high BMI may decrease the risk of MSI endometrial tumors (22, 23). In our study, the mean (32.6) or median (32.4) BMI for MSI cases was slightly higher than that for MSS cases (31.8 and 30.7, respectively). The inclusion of HNPCC-related endometrial cancers, which are characterized as MSI, in the 2 previous case series may explain the discrepancy in results, since BMI may be less important etiologically for women with a hereditary syndrome. Additionally, discrepancies in results are not surprising, as case-series investigators often recruit highly selected study populations that may have particular referral biases and may lack a comparison group.
Different biological mechanisms have been proposed to explain the increased risk of endometrial cancer associated with BMI, including hormonal imbalance and inflammation (5). The mechanism for the increased risk of MSI endometrial tumors as compared with MSS endometrial tumors associated with obesity is not known. Previous studies of colon cancer have suggested that higher estrogen levels resulting from obesity may prevent MSI tumors (40, 41). However, in our study, we observed that obesity was associated with a higher risk of MSI endometrial tumors than of MSS endometrial tumors. It is possible that elevated estrogen levels may increase the risks of colon cancer and endometrial cancer through different mechanisms. Estrogen may prevent MSI colon tumors, possibly by activating one of the MMR genes in the colon. In the hormone-sensitive endometrium, estrogen may act as a general mitogen increasing the risks of both MSS and MSI tumors, but it may be particularly potent if the MMR machinery has already been compromised. The MSI phenotype for obese endometrial cancer patients may be an early event resulting from chronic systemic inflammation associated with obesity that induces MMR abnormalities (42) or from other unknown mechanisms. Subsequently, the combination of errors in the MMR machinery and the rapid cellular proliferation due to estrogen activation may make obese women particularly susceptible to MSI endometrial tumors as compared with MSS endometrial tumors. The observation that the MSI phenotype is an early event in type 1 endometrial cancer (43), which is associated with BMI, provides support for this mechanism. However, this mechanism is largely speculative, and future studies are warranted to understand the underlying biological mechanism that would explain the higher risk of MSI endometrial tumors than of MSS endometrial tumors in obese women.
The strengths of this study include the large sample size, the identification of incident cancer cases from a population-based cancer registry, the use of the Amsterdam II criteria to exclude HNPCC-associated cancers, the adjustment for important confounders in statistical models, and the validation of the microsatellite status of a 10% random sample of the cases. The study's limitations include the lower response rate for controls, which might have resulted in selection bias. However, a comparison of our control sample with a population-based sample of Alberta women revealed no major selection bias (25). Additionally, although we combined MSI-low cases (1 mismatch error) with microsatellite-stable cases (no mismatch errors) and grouped them together as MSS cases, an analysis excluding MSI-low cases did not alter the findings of this study. Furthermore, self-reported weight, especially at young adult ages, may be difficult to recall. Presumably, such misclassification will be nondifferential and will attenuate the risk estimates, implying that our observed positive associations with risk may be underestimates. Although the results for additional adjustment for waist circumference for the association between BMI and MSS/MSI tumors may represent overadjustment, we still observed a stronger risk for MSI tumors than for MSS tumors (despite the attenuation of effects). Thus, the results for the additional adjustment do not undermine our conclusion that BMI has a stronger association with MSI endometrial tumors than with MSS endometrial tumors.
In summary, our findings provide additional evidence supporting an increased risk of overall endometrial cancer associated with recent and adult-life anthropometric measures. Our novel findings indicate that these anthropometric characteristics are associated with both MSI and MSS sporadic endometrial cancer. Additionally, women with a high BMI had an elevated risk of both the MSI and MSS subtypes, but the risk was particularly strong for MSI sporadic endometrial cancer. Future studies are needed to understand the biological mechanisms underlying this difference.
ACKNOWLEDGMENTS
Author affiliations: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (Ernest K. Amankwah); Population Health Research–Cancer Care, Alberta Health Services, Calgary, Alberta, Canada (Christine M. Friedenreich, Thomas Speidel, Annie R. Langley, Linda S. Cook); Department of Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (Christine M. Friedenreich, Linda S. Cook); Department of Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (Christine M. Friedenreich, Wahida Rahman); Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (Anthony M. Magliocco); Department of Statistics, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada (Rollin Brant); Behavioural Medicine Laboratory, Faculty of Physical Education and Recreation, University of Alberta, Edmonton, Alberta, Canada (Kerry S. Courneya); and Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico (Linda S. Cook).
This study was funded by grants from the National Cancer Institute of Canada and the Canadian Institutes of Health Research. E.K.A. was supported by a Health Research Studentship from the Alberta Heritage Foundation for Medical Research (AHFMR) during the conduct of the study. He is now supported by a cancer prevention fellowship from the US National Cancer Institute (grant R25T CA147832). L.C. held a Canada Research Chair and a career award from the AHFMR. C.M.F. held career awards from the Canadian Institutes of Health Research and the AHFMR. K.S.C. currently holds a Canada Research Chair.
We thank all of the staff at Alberta Health Services–Cancer Care for data and specimen collection; the collaborating hospitals and pathology laboratories; the University of Calgary DNA Core Facility for running polymerase chain reaction products on their ABI sequencer (Applied Biosystems Ltd., Mississauga, Ontario, Canada); and Kwabena Amankwah for assistance with tables.
Conflict of interest: none declared.
Appendix Table 1.
Associations Between Current Weight and Body Mass Index and Overall, MSS, and MSI Endometrial Cancer, Adjusted for Current Weight and/or Weight at Age 20 Years, Alberta, Canada, 2002–2006
| Variable | All Cases (n = 467) vs. Controls (n = 1,030) |
MSS Cases (n = 337) vs. Controls |
MSI Cases (n = 130) vs. Controls |
P-heta | |||
|---|---|---|---|---|---|---|---|
| ORb | 95% CI | ORb | 95% CI | ORb | 95% CI | ||
| Current weight, kg | |||||||
| ≤63.1 | 1.00 | 1.00 | 1.00 | ||||
| >63.1–71.5 | 0.72 | 0.48, 1.07 | 0.64 | 0.41, 1.00 | 1.01 | 0.50, 2.03 | 0.26 |
| >71.5–81.8 | 0.93 | 0.62, 1.39 | 0.85 | 0.54, 1.32 | 1.2 | 0.61, 2.46 | 0.34 |
| >81.8 | 1.23 | 0.74, 2.04 | 1.11 | 0.63, 1.94 | 1.66 | 0.72, 3.79 | 0.37 |
| P-trend | 0.37 | 0.63 | 0.24 | ||||
| Body mass indexc | |||||||
| <25 | 1.00 | 1.00 | 1.00 | ||||
| 25–<30 | 0.88 | 0.62, 1.24 | 0.79 | 0.49, 1.07 | 1.55 | 0.81, 2.94 | 0.034 |
| ≥30 | 1.04 | 0.66, 1.64 | 0.80 | 0.48, 1.32 | 2.23 | 1.03, 4.79 | 0.014 |
| P-trend | 0.86 | 0.38 | 0.05 | ||||
Abbreviations: CI, confidence interval; MSI, microsatellite-instable; MSS, microsatellite-stable; OR, odds ratio.
a P value for heterogeneity between odds ratios for MSS and MSI, both compared with controls.
b Odds ratios were adjusted for reference age (years; continuous), residence type (rural or urban), age at menarche (≤12 years or >12 years), menopausal status/hormone use (peri- or postmenopausal/never use, peri- or postmenopausal/use of estrogen only, peri- or postmenopausal/any use of estrogen plus progesterone, or peri- or postmenopausal/other menopausal hormone use or premenopausal hormone use), parity/age at first pregnancy (nulliparous, 1–2/≤25 years, 1–2/>25 years, >2/≤25 years, or >2/>25 years), hypertension (ever or never), and waist circumference (cm; continuous).
c Weight (kg)/height (m)2.
Appendix Table 2.
Associations Between Weight at Age 20 Years and Weight Gain Since Age 20 Years and Overall, MSS, and MSI Endometrial Cancer, Adjusted for Current Weight and/or Weight at Age 20 Years, Alberta, Canada, 2002–2006
| Variable | All Cases (n = 467) vs. Controls (n = 1,030) |
MSS Cases (n = 337) vs. Controls |
MSI Cases (n = 130) vs. Controls |
P-heta | |||
|---|---|---|---|---|---|---|---|
| ORb | 95% CI | ORb | 95% CI | ORb | 95% CI | ||
| Weight at age 20 years, kg | |||||||
| ≤49.9 | 1.00 | 1.00 | 1.00 | ||||
| >49.9–54.4 | 1.10 | 0.75, 1.61 | 1.30 | 0.85, 1.98 | 0.67 | 0.33, 1.33 | 0.08 |
| >54.4–59.0 | 0.99 | 0.72, 1.37 | 1.00 | 0.69, 1.44 | 0.98 | 0.59, 1.62 | 0.94 |
| >59.0 | 0.93 | 0.65, 1.33 | 1.04 | 0.70, 1.55 | 0.70 | 0.39, 1.24 | 0.21 |
| P-trend | 0.63 | 0.90 | 0.39 | ||||
| Weight gain since age 20 years, kg | |||||||
| ≤8.8 | 1.00 | 1.00 | 1.00 | ||||
| >8.8–16.8 | 0.96 | 0.65, 1.40 | 1.02 | 0.67, 1.57 | 0.79 | 0.40, 1.55 | 0.49 |
| 1.26c | 0.86, 1.85 | 1.35c | 0.88, 2.07 | 1.03c | 0.52, 2.04 | 0.49 | |
| >16.8–25.9 | 0.95 | 0.64, 1.40 | 0.96 | 0.62, 1.48 | 0.92 | 0.48, 1.76 | 0.91 |
| 1.58c | 1.10, 2.29 | 1.60c | 1.06, 2.42 | 1.54c | 0.82, 2.88 | 0.91 | |
| >25.9 | 1.11 | 0.70, 1.76 | 1.04 | 0.62, 1.73 | 1.31 | 0.63, 2.73 | 0.56 |
| 3.03c | 2.15, 4.28 | 2.82c | 1.91, 4.15 | 3.62c | 2.06, 6.38 | 0.43 | |
| P-trend | 0.72, <0.001c | 0.99, <0.001c | 0.41, <0.001c | ||||
Abbreviations: CI, confidence interval; MSI, microsatellite-instable; MSS, microsatellite-stable; OR, odds ratio.
a P value for heterogeneity between odds ratios for MSS and MSI, both compared with controls.
b Odds ratios were adjusted for reference age (years; continuous), residence type (rural or urban), age at menarche (≤12 years or >12 years), menopausal status/hormone use (peri- or postmenopausal/never use, peri- or postmenopausal/use of estrogen only, peri- or postmenopausal/any use of estrogen plus progesterone, or peri- or postmenopausal/other menopausal hormone use or premenopausal hormone use), parity/age at first pregnancy (nulliparous, 1–2/≤25 years, 1–2/>25 years, >2/≤25 years, or >2/>25 years), hypertension (ever or never), and current weight (kg; continuous).
c Additionally adjusted for weight at age 20 years (kg; continuous).
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