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Menarche age, parity influence endometrial cancer risk for women with Lynch syndrome
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Several hormonal factors — including later age at menarche, parity and hormonal contraceptive use — reduced the risk for endometrial cancer in women with Lynch syndrome, according to study results.
Women with Lynch syndrome — an autosomal dominant disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes — account for 2% to 5% of endometrial cancer cases, according to study background. Depending on the location of the gene mutation, the cumulative risk for developing endometrial cancer by 70 years may be as high as 15% to 30% in these women.
Hysterectomy currently serves as the only recommended procedure for reducing endometrial cancer risk in women with Lynch syndrome.
Aung Ko Win, MBBS, PhD, MPH, a genetic epidemiologist at the Melbourne School of Population and Global Health at the University of Melbourne in Victoria, Australia, and colleagues conducted a retrospective cohort study to examine the association between hormonal factors and endometrial cancer risk among women with Lynch syndrome.
The analysis included data from 1,128 women with Lynch syndrome (median age, 40 years; range, 18-86) identified through the Colon Cancer Family Registry. The researchers implemented a weighted cohort approach to analyze data, recruiting participants from centers in the U.S., Australia, Canada and New Zealand between 1997 and 2012.
Of the overall cohort, 133 women received a diagnosis of endometrial cancer (incidence per 100 person-years, 0.29; 95% CI, 0.24-0.34).
The researchers identified several hormonal factors associated with a lower risk for endometrial cancer among women with Lynch syndrome. These included menarche at 13 years or older (HR = 0.7; 95% CI, 0.44-1.11), one or more live births (HR = 0.21; 95% CI, 0.1-0.42) and the use of hormonal contraceptive for 1 or more years (HR = 0.39; 95% CI, 0.23-0.64).
Other hormonal factors — such as age at first and last live birth, age at menopause and postmenopausal hormone use — did not reach statistical significance for affecting the risk for endometrial cancer.
The researchers acknowledged limitations of their study, including the possibility for errors related to the self-reporting of data. The researchers also did not include data on BMI — a strong and consistent risk factor for endometrial cancer — in over half the study population.
“For women with an MMR gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk for endometrial cancer,” Win and colleagues concluded. “These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with an MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.” – by Cameron Kelsall
Disclosure: Win reports no relevant financial disclosures. One researcher reports a scientific advisory board membership with Cancer Prevention Pharmaceuticals and EXACT Sciences Inc.
Perspective
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Charis Eng, MD, PhD
In women with Lynch syndrome, the 40% lifetime risk for endometrial cancer is as high as their lifetime risk for colorectal cancer. Lynch syndrome — caused by germline mutations in genes encoding mismatch repair enzymes, most commonly, MLH1, MSH2 and MSH6 — confers a high risk for colorectal, endometrial, ovarian and other cancers. Factors that modify risks for component cancers impact clinical practice. Dashti and colleagues analyzed a retrospective cohort of 1,128 women in the Colon Cancer Family Registry, which accrued from centers across North America, Australia and New Zealand between 1997 and 2012. Researchers found that late age at menarche, parity (> 1) and hormonal contraceptive use (> 1 year) were associated with lower risk for endometrial cancer. In contrast, there was no association with age of first and last live birth, age at menopause, and postmenopausal hormone use. The authors found that the strengths and directions of associations in women with Lynch syndrome were no different than those in the general population, which could result in advice easily utilized in clinical practice.Somatic alterations in the PTEN tumor suppressor gene are one of the most common etiologies for sporadic endometrial cancers. Interestingly, a study of 41 Lynch syndrome-associated endometrial cancers revealed 68% with absent or weak expression of PTEN. Of 20 available decreased/absent PTEN-expressing tumors, 85% were found to carry somatic PTEN frameshift mutations. In an unrelated study on sporadic endometrial cancers, progesterone exposure was shown to be associated with increased PTEN expression. It is possible that the hormonal contraceptive usage associated with decreased risks for endometrial cancer in women with Lynch syndrome might be explained by the progesterone component increasing PTEN levels in the endometrium and, hence, suppressing carcinogenesis.
References:
Mutter GL, et al. J Clin Endocrinol Metab. 2000;doi:10.1210/jcem.85.6.6652.Zhou XP, et al. Hum Mol Genet. 2002;doi:10.1093/hmg/11.4.445.
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