Endometrial cancer risk factors among lynch syndrome women: a retrospective cohort study

ABSTRACT BACKGROUND: Lynch syndrome (LS) is associated with a significant lifetime risk of endometrial cancer (EC). There are limited data on factors modifying the EC risk in LS patients.

METHODS: The study cohort included 136 LS mutation-positive women. Exposure data were collected by postal questionnaires. Cox regression model was used to estimate the associations between

lifestyle, hormonal, reproductive and medical factors and the risk of EC. RESULTS: Increased EC risk was associated with type II diabetes and hypercholesterolaemia in univariable (HR 3.21,

(95% CI 1.34–7.78), _P_=0.009 and HR 2.08, (95% CI 1.11–3.90), _P_=0.02; respectively) and with diabetes and duration of hormone replacement therapy (HRT) in multivariable analysis (HR 4.18

(95% CI 1.52–11.52), _P_=0.006 and HR 1.07 (95% CI 1.02–1.13), _P_=0.010; respectively). CONCLUSIONS: Prevention of diabetes and avoiding long-duration HRT are potential targets for

reduction of EC risk in women with LS. SIMILAR CONTENT BEING VIEWED BY OTHERS ASSOCIATION OF ENDOMETRIAL CANCER RISK WITH HYPERTENSION- AN UPDATED META-ANALYSIS OF OBSERVATIONAL STUDIES

Article Open access 22 October 2024 GENETIC RISK IMPACTS THE ASSOCIATION OF MENOPAUSAL HORMONE THERAPY WITH COLORECTAL CANCER RISK Article Open access 01 April 2024 MENOPAUSAL HORMONE

THERAPY USE AND RISK OF OVARIAN CANCER BY RACE: THE OVARIAN CANCER IN WOMEN OF AFRICAN ANCESTRY CONSORTIUM Article 21 October 2023 MAIN Lynch syndrome (LS) is a cancer predisposition

syndrome with autosomal-dominant inheritance pattern caused by germ-line mutations in DNA mismatch repair (MMR) genes _MLH1_, _MSH2_, _MSH6_ and _PMS2_ (Vasen et al, 1999). LS is associated

with significantly increased lifetime risks of both colorectal and endometrial cancer (EC), ranging from 20% to 51% depending on the type of the mutation (Møller et al, 2015). Factors

increasing EC risk in general population all relate to conditions of oestrogen dominance over progesterone. EC risk has been shown to increase with nulliparity, early age at menarche, late

age at menopause, obesity, metabolic syndrome, ovulation failure, non-use of hormonal contraceptives, and oestrogen or sequential hormone replacement therapy (HRT) (Ali, 2014; Barry et al,

2014; Trabert et al, 2015). Data on the influence of these risk factors on EC risk of genetically predisposed LS women are, however, limited. An intervention study of oral contraceptive and

medroxyprogesterone acetate in LS women suggested a protective effect on endometrial proliferation similar to the general population (Lu et al, 2013). This was further supported by a recent

large retrospective study, where EC risk in LS women decreased with parity, use of hormonal contraceptives and later age at menarche (Dashti et al, 2015). The association of high body mass

index (BMI) and other metabolic syndrome-related factors with EC risk of LS women is not clear. Studies addressing the association of BMI with MMR protein expression or microsatellite

instability in unselected EC have been contradictory (McCourt et al, 2007; Cohn et al, 2008; Gonzalez et al, 2012; Joehlin-Price et al, 2014). Only few comprehensive studies have been

conducted in well-characterised study populations with germ-line mutation testing. According to these studies, BMI may not be associated with EC risk among LS women (Win et al, 2011; Dashti

et al, 2015). To date, hysterectomy provides the only means for EC risk reduction or prevention in high-risk women. Therefore, research on the impact of environmental factors on EC risk in

LS women is needed. Here we have estimated the associations between lifestyle, hormonal, reproductive and medical factors and the risk of EC in a cohort of MMR germ-line mutation carrier

women. MATERIALS AND METHODS STUDY PATIENTS This retrospective cohort study was carried out in Tampere University Hospital (TAUH), Finland. Study cohort included Finnish women with inherited

pathogenic MMR gene mutation identified from the nationwide Finnish LS Registry (Jarvinen et al, 2009). The Finnish LS Registry consists data of original research cohort including 81

kindreds ascertained through family history strongly suggestive of LS and clinic-based cohort including patients referred to clinical genetic units of five University hospitals in Finland

for suspected LS (Mecklin et al, 1987; Gylling et al, 2009). The index patients belonging to the research cohort have been directly tested for germ-line MMR mutations without prescreening

for MMR protein loss in the tumours. Patients of clinic-based cohort have been screened for MMR deficiency in tumour tissue prior to germ-line testing from blood samples. Counselling and

possible germ-line mutation testing have been systematically offered for family members of index patients up to second- or even to third-degree relatives. Mutation analyses have been

performed by direct exon sequencing or by multiplex ligation-dependent probe amplification (Gylling et al, 2009). The pathogenicity of MMR gene sequence variants has been evaluated by

InSiGHT criteria (Thompson et al, 2014). At present, the Finnish LS Registry includes 260 families and approximately 1400 verified germ-line MMR mutation carriers (http://www.hnpcc.fi/).

Questionnaires addressing lifestyle factors, medical and reproductive history were mailed to 223 MMR germ-line mutation carrier women living across Finland and having previously consented

for LS Registry inquiries. Content of postal questionnaires is summarised in Table 1. Questionnaires were re-sent to non-responding patients in 6 months after first mailing. EC diagnoses

were confirmed from the pathology reports and medical records obtained from district hospitals. Informed consent was obtained from all study participants and the study protocol was approved

by TAUH Ethical Committee. STATISTICAL ANALYSIS SPSS statistics software (version 22, IBM, Armonk, NY, USA) was used for the statistical analyses. Cox regression model was used to estimate

the associations between parity, age at menarche and menopause, duration of HRT or hormonal contraception, BMI, annual weight change, alcohol consumption and the risk of EC in LS women. Age

was used as a timescale for EC risk estimation. The time at risk was considered to start from birth and end at the diagnosis of EC, prophylactic hysterectomy or the time of the survey,

whichever occurred first. For the univariable analyses, age at menarche and menopause, BMI, annual weight change, duration of hormonal contraception and HRT were divided into two categories

by the median values of the variables. These variables were also analysed as continuous variables in the regression model. In addition, BMI was also categorised using cutoff points 25

(=overweight) and 30 (=obese). The comparison of BMI as a continuous variable between diabetic and non-diabetic patients was performed using nonparametric testing. As the LS women in the

study were ascertained from multiple case cancer families or because of EC diagnosis, the selection of women may not have been random with respect to disease status. Therefore, ascertainment

was adjusted for in the multivariable analyses by taking into account the time of germ-line testing with respect to the end of time at EC risk (i.e., germ-line testing performed before EC

diagnosis, prophylactic hysterectomy or survey in healthy non-hysterectomised women compared with germ-line mutation testing after EC diagnosis or prophylactic hysterectomy). Parity, age at

menarche and duration of hormonal contraceptive use as continuous variables were also adjusted for in the multivariable analysis as they have been previously reported to associate with EC

risk in LS women (Dashti et al, 2015). Two-tailed _P_ values of <0.05 were considered as statistically significant. RESULTS One hundred and thirty-six women returned the questionnaire

resulting in a 61% response rate. Median age at survey was 58 years (range 29–85). Distribution of the different germ-line mutations was as follows: 82.4% of _MLH1_, 11% of _MSH2_, and 6.6%

of _MSH6_ mutations. Fifty women (36.8%) had been diagnosed with EC at median age of 49.5 years. Prophylactic surgery had been performed in 52 out of 86 (60.5%) of EC unaffected women at

median age of 45 years. Characteristics of the study patients and exposure data are summarised in Table 2. In univariable Cox regression analysis, non-insulin-dependent diabetes and

hypercholesterolaemia were associated with an elevated risk of EC (HR 3.21 (95% CI 1.34–7.78), _P_=0.009; HR 2.08 (95% CI 1.11–3.90), _P_=0.02; respectively). Diabetic LS women were more

overweight than non-diabetic LS women at survey (median BMI 29.7 _vs_ 25.0, _P_=0.012, Mann–Whitney _U_-test), but BMI at the age of 18 or 40 years or at survey did not associate with the

risk of EC (HR 1.03, (95% CI 0.91–1.17), _P_=0.6; HR 1.04, (95% CI 0.98–1.11), _P_=0.19; HR 1.02 (95% CI 0.97–1.08), _P_=0.42; respectively). Among ever users of HRT (n=61), the duration of

use (>9 years) showed a trend for association with EC risk (HR 2.03 (95% CI 0.89–4.62), _P_=0.09). History of endometriosis showed also a trend for association with EC risk (HR 1.96 (95%

CI 0.90–4.28), _P_=0.09). In multivariable Cox regression model, diabetes and duration of HRT use were associated with a statistically significant increase in the risk of EC (HR 4.18 (95% CI

1.52–11.52), _P_=0.006; HR 1.07 (95% CI 1.02–1.13), _P_=0.010; respectively). Summary of univariable and multivariable Cox regression analyses is presented in Table 3. DISCUSSION We report

here the associations between EC risk and lifestyle, medical and hormonal factors in a retrospective cohort of verified MMR mutation carriers. These findings suggest that type II diabetes

and postmenopausal hormone therapy may associate with an elevated risk of EC in LS. Even though diabetic LS women were more overweight than non-diabetic women at survey, BMI at any time

point or annual weight change did not associate with the risk of EC. Our results are in contrast to the previous observations of BMI as an EC risk factor in general population (Jenabi and

Poorolajal, 2015) but are in line with studies reporting no association among MMR mutation carriers (Win et al, 2011; Dashti et al, 2015). Our data regarding BMI therefore partially supports

the view that pathogenesis of EC in LS could be independent of oestrogenic pathway (Win et al, 2011). However, hormonal risk factors have been shown to act similarly on EC risk in both

general and LS population (Lu et al, 2013; Ali, 2014; Dashti et al, 2015). Recently, a large retrospective cohort study showed a reduction of EC risk in LS women with longer use of hormonal

contraceptives, later age at menarche and parity (Dashti et al, 2015). These findings were not repeated in our cohort possibly owing to different ethnic background or smaller sample size and

therefore lack of statistical power. An association between postmenopausal HRT and EC risk was detected in multivariable analysis, which can be interpreted as in-line with previous findings

concerning the influence of hormonal factors. However, it should be noted that neither the type of hormonal contraceptives nor the type of HRT (i.e., unopposed oestrogen or oestrogen

opposed by sequential or continuous progestin) was specified in our study. The reported positive associations between diabetes and HRT use and increased EC risk are novel in verified MMR

germ-line mutation carriers and are in line with studies regarding EC risk in general population (Trabert et al, 2013; Liao et al, 2014). In the present study, five out of six women had been

diagnosed with diabetes prior to EC diagnosis (the mean time interval between diabetes and EC diagnoses was 5 years). All reported cases of diabetes in the present study were non-insulin

dependent, which generally are strongly linked to obesity (Nathan, 2015). Even if BMI itself may not affect the EC risk in MMR mutation carriers, the positive association between diabetes

and EC risk suggests weight control to be beneficial for LS women in prevention of diabetes and therefore also EC. There are several limitations to the study. The sample size of the cohort

was relatively small but, on the other hand, included only verified MMR mutation carriers. Exposure data were collected by self-reported questionnaires possibly causing bias. For instance

patients older at the time of survey had to recall their weight and duration of hormonal contraception back a long time. Nevertheless, it has been shown that recalled weight measures

actually correlate well (Perry et al, 1995). Finally, the cohort was subjected to potential immortal bias and may have been overrepresented with EC cases of a more favourable outcome, as

they represent survivors who may have been fit enough to complete the questionnaires. In conclusion, our data suggest that diabetes and use of postmenopausal HRT may increase the risk of EC

in LS women. If these results are replicated, lifestyle modifications aiming at prevention of diabetes may be beneficial for MMR mutation carrier women in terms of reduction of EC risk. As

regards to postmenopausal HRT, the present results imply that long-term HRT should not be encouraged. CHANGE HISTORY * _ 26 JULY 2016 This paper was modified 12 months after initial

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Download references ACKNOWLEDGEMENTS This study was supported by the Tampere Medical Society (to SS), the Finnish Medical Association (to SS), the Finnish Cancer Foundation (to JM and J-PM)

and the Jane and Aatos Erkko Foundation (to J-PM). We thank Professor Eero Pukkala from the Finnish Cancer Registry for valuable advice with the statistical analysis. AUTHOR INFORMATION

Author notes * Synnöve Staff and Mari Aaltonen: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Obstetrics and Gynecology, Tampere University

Hospital, Tampere, Finland Synnöve Staff, Mari Aaltonen & Johanna Mäenpää * Laboratory of Cancer Biology, BioMediTech, University of Tampere, Tampere, Finland Synnöve Staff * School of

Health Sciences, University of Tampere, Tampere, Finland Heini Huhtala * Department of Education and Research, Jyväskylä Central Hospital, Jyväskylä, Finland Kirsi Pylvänäinen * Department

of Surgery, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland Jukka-Pekka Mecklin * School of Medicine, University of Tampere, Tampere, Finland Johanna Mäenpää

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Staff, S., Aaltonen, M., Huhtala, H. _et al._ Endometrial cancer risk factors among Lynch syndrome women: a retrospective cohort study. _Br J

Cancer_ 115, 375–381 (2016). https://doi.org/10.1038/bjc.2016.193 Download citation * Received: 14 March 2016 * Revised: 18 May 2016 * Accepted: 24 May 2016 * Published: 23 June 2016 *

Issue Date: 26 July 2016 * DOI: https://doi.org/10.1038/bjc.2016.193 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry,

a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Lynch syndrome * endometrial

cancer * risk * lifestyle * medical history * reproductive history