{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands"
      ],
      "name": "Maartje A C Schreurs"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands"
      ],
      "name": "Antoinette Hollestelle"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Muriel A Adank"
    },
    {
      "affiliations": [
        "Division of Reproductive Endocrinology and Infertility, Erasmus MC, Rotterdam, The Netherlands"
      ],
      "name": "Yvonne Louwers"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Christi J van Asperen"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands",
        "Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands"
      ],
      "name": "Margreet G E M Ausems"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Irma van de Beek"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands"
      ],
      "name": "Margriet J Collee"
    },
    {
      "affiliations": [
        "Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands"
      ],
      "name": "Charlotte J Dommering"
    },
    {
      "affiliations": [
        "Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands"
      ],
      "name": "Encarna B Gómez García"
    },
    {
      "affiliations": [
        "Radboud University Medical Center, Nijmegen, The Netherlands"
      ],
      "name": "Marijke R Wevers"
    },
    {
      "affiliations": [
        "Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Emma M Vieveen"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynecology, University of Groningen, Groningen, The Netherlands"
      ],
      "name": "Refika Yigit"
    },
    {
      "affiliations": [
        "Molecular Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands"
      ],
      "name": "Marjanka K Schmidt"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands"
      ],
      "name": "Jenny A Visser"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands",
        "Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands"
      ],
      "name": "Maartje J Hooning"
    },
    {
      "affiliations": [],
      "name": "On behalf of Hebon"
    }
  ],
  "title": "Later age of natural menopause among women with the pathogenic CHEK2 c.1100delC variant: a validation study",
  "uid": "4bab8aa9-5889-5468-b0de-75e8cde24146"
}