Later age of natural menopause among women with the pathogenic CHEK2 c.1100delC variant: a validation study

Background The average age of natural menopause (ANM) for European women is 50-52 years. Reproductive risk and lifestyle factors have been found to be associated with ANM. Furthermore, a genome-wide association study found that women with a CHEK2 variant reach ANM 3.49 years later than women without a CHEK2 variant ('non-carriers'). With this study, we aim to validate this association within CHEK2 c.1100delC families.Methods As part of the HEreditary Breast and Ovarian cancer Netherlands (Hebon) study, all women who underwent genetic testing for pathogenic variants associated with breast or ovarian cancer were invited to participate and complete a questionnaire on established risk factors. We compared the reported ANM between groups and within selected birth cohorts. HRs and 95% CIs for the association of CHEK2 status with ANM were estimated via Cox regression models, adjusted for age of menarche, parity, smoking status and hormonal contraceptive use.Results We included 661 CHEK2 c.1100delC heterozygotes, 175 non-carrier relatives and 8839 unrelated non-carriers. CHEK2 c.1100delC women reached ANM at a significantly later age (51.8 +/- 4.8 years) compared with non-carrier relatives (50.3 +/- 4.0 years) and unrelated non-carriers (49.6 +/- 4.8 years). Similar patterns were found within the birth cohorts. In Cox regression analysis, heterozygotes were associated with a later ANM compared with unrelated non-carriers (HR 1.58; 95% CI 1.21 to 2.08) and non-carrier relatives (HR 1.83; 95% CI 1.13 to 2.95).Conclusion CHEK2 c.1100delC is associated with 1.5-2.2 years later ANM compared with non-carriers, underlining the independence of CHEK2 c.1100delC irrespective of heritability of ANM within families.