Hormonal Factors and Endometrial Cancer Risk in Lynch Syndrome

Elizabeth Lai, Mercer University College of Pharmacy

A review of Lynch syndrome (LS) states that LS is an inherited autosomal dominant for syndrome cancers in the family pedigree.  Diagnosis of LS is completed by germline testing of a mutation in a deoxyribonucleic acid (DNA) mismatch repair gene (42).1  Colorectal cancer is the most common form of cancer seen in LS patients, which is also characterized by cancers of the endometrium and ovary.2

According to a review of molecular carcinogenesis of EC, most ECs that are Type I carcinomas are based on an estrogen-related pathway.  Type II carcinomas are suggested to have an estrogen-unrelated pathway and occur in older women.3  Many women with LS present with EC at age 50 years or older and the risk for LS in those with EC less than 50 years is increased by 9%.4

Title: Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome
Design Retrospective cohort study; N = 1128
Objective To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome
Study Groups No endometrial cancer and endometrial cancer
Methods Women were recruited by the Colon Cancer Family Registry and permission was sought to contact relatives and seek their enrollment in the registry.  First-degree relatives of probands (those with recent diagnosis of colorectal cancer) were recruited in population-based families, and included recruitment of distant relatives.  Clinic-based families included recruitment of second-degree relatives of those affected.  Follow-up occurred every 5 years after baseline.
Duration 1997 – 2012
Primary Outcome Measure Self-reported diagnosis of endometrial cancer
Baseline Characteristics Number (%)
No Endometrial cancer (n = 995) Endometrial Cancer (n = 133) Total (N = 1128)
White 923 (92.8) 128 (96.1) 1051 (93.2)
Other 51 (5.1) 4 (3.0) 55 (4.9)
Missing data 21 (2.1) 1 (0.8) 22 (1.9)
Ascertainment method
Clinic 742 (74.6) 102 (76.7) 844 (74.8)
Population 253 (25.4) 31 (23.3) 284 (25.2)
Mean (standard deviation) 39.9 (11.4) 45.9 (8.2) 40.6 (11.3)
Median (range) 40 (18-86) 46 (25-68) 40 (18-86)
Family history of colorectal or endometrial cancer
No family history 178 (17.9) 21 (15.8) 199 (17.6)
First-degree relative 137 (13.8) 28 (21.1) 165 (14.6)
Second-degree relative 79 (7.9) 7 (21.1) 86 (7.6)
First- and second-degree relative 601 (60.4) 77 (57.9) 678 (60.1)
Results No p-values were reported.
No Endometrial cancer (n = 995) (%) Endometrial Cancer (n = 133) (%) Total (N = 1128) (%)
Australia or New Zealand 557 (56.0) 52 (39.1) 609 (54.0)
United States 290 (29.2) 50 (37.6) 340 (30.1)
Canada 148 (14.9) 31 (23.3) 179 (15.9)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer.  These directions and strengths of associations were similar to those for the general population.  If replicated, these findings suggest that women with a mismatch repair gene mutations may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.

The study revealed that an inverse association was observed between risk of endometrial cancer with MMR gene mutation and late menarche, increased parity, and use of HC.  Lack of observed association between EC and PMH use may be due to a poor statistical power.  There was no statistical significance between age of menopause and EC risk in Lynch syndrome or between EC risk and age at first and last live birth in Lynch syndrome.  Errors in measurement of variables may have occurred in self-reported questionnaires, assuming continuous use of HC and PMH, overestimating years of hormone use, or EC diagnosis before interview.


  1. Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009 July ; 76(1): 1–18.
  2. Tafe LJ, Riggs ER, Tsongalis GJ. Lynch Syndrome Presenting as Endometrial Cancer. Clin Chem. 2014 Jan;60(1):111-21.
  3. Liu FS. Estrogens, MSI and Lynch syndrome-associated tumors. Taiwan J Obstet Gynecol. 2007 Mar;46(1):26-32.
  4. Garg K, Soslow RA. Endometrial carcinoma in women aged 40 years and younger. Arch Pathol Lab Med. 2014 Mar;138(3):335-42.

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