Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML

Janiszewska, Hanna; Bąk, Aneta; Skonieczka, Katarzyna; Jaśkowiec, Anna; Kiełbiński, Marek; Jachalska, Anna; Czyżewska, Maria; Jaźwiec, Bożena; Kuliszkiewicz‐Janus, Małgorzata; Czyż, Jarosław; Kuliczkowski, Kazimierz; Haus, Olga

doi:10.1016/j.leukres.2018.05.013

Cited by 24 publications

(15 citation statements)

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“…Besides breast cancer and related diagnoses, rare damaging variants in CHEK2 were also associated with prostate cancer, which has been previously reported 28 . CHEK2 variants also associated with myeloid leukemia, consistent with reports that CHEK2 coding variants associate with myelodysplastic syndrome 29 .…”

Section: Other Associations With Menopause Timing-associated Genessupporting

confidence: 89%

“…In addition to discovering associations between rare damaging variants in CHEK2 with menopause timing, and replicating known associations with breast cancer 30 , prostate cancer 28 , and myeloid leukemia 29 , we find associations with many hematological measurements such as increased leukocyte counts and platelet crit, and associations with several diagnoses: polycystic ovary syndrome (PCOS), uterine fibroids, prostate hyperplasia, and seborrheic keratosis. These hematological associations were first reported in an earlier analysis of the UK Biobank exome data and were hypothesized to be secondary to cancer treatment 14 ; however, we find that they exist in individuals with no diagnosed neoplasm.…”

Section: Novel Chek2 Biologysupporting

confidence: 59%

“…They are unlikely to be secondary to menopause timing, as they persist in both men and women, and are seen among women even when correcting for menopause status at the time of the blood assay. It is more likely, therefore, that these hematological changes arise through the same mechanisms that predispose to myelodysplastic syndrome in CHEK2 mutation carriers 29 . After TP53, CHEK2 was identified as a second causal gene for Li-Fraumeni syndrome (MIM: 609265), which involves risk for many cancers 35; 36 .…”

Section: Novel Chek2 Biologymentioning

confidence: 99%

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Rare coding variants in five DNA damage repair genes associate with timing of natural menopause

Ward

Deaton

et al. 2021

Preprint

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The age of menopause is associated with fertility and disease risk, and its genetic control is of great interest. We used whole-exome sequences from 119,992 women in the UK Biobank to test for associations between rare damaging variants and age at natural menopause. Rare damaging variants in three genes significantly associated with menopause: CHEK2 (p = 6.2 × 10-51) and DCLRE1A (p = 1.2 × 10-12) with later menopause and TOP3A (p = 8.8 × 10-8) with earlier menopause. Two additional genes were suggestive: RAD54L (p = 2.3 × 10-6) with later menopause and HROB (p = 2.7 × 10-6) with earlier menopause. In a follow-up analysis of repeated questionnaires in women who were initially pre-menopausal, CHEK2, TOP3A, and RAD54L genotype associated with subsequent menopause. Consistent with previous GWAS, all five genes are involved in the DNA-damage repair pathway. Phenome-wide scans across 363,977 men and women revealed that in addition to known associations with cancers and blood cell counts, rare variants in CHEK2 also associated with increased risk of uterine fibroids, polycystic ovary syndrome, and prostate hypertrophy; these associations are not shared with higher-penetrance breast cancer genes. Causal mediation analysis suggests that approximately 8% of the breast cancer risk conferred by CHEK2 pathogenic variants after menopause is mediated through delayed menopause.

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Section: Other Associations With Menopause Timing-associated Genessupporting

confidence: 89%

Section: Novel Chek2 Biologysupporting

confidence: 59%

Section: Novel Chek2 Biologymentioning

confidence: 99%

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Rare coding variants in five DNA damage repair genes associate with timing of natural menopause

Ward

Deaton

et al. 2021

Preprint

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“…We suspected a possible pathogenic role for CHEK2 c.475T > C (Y159H) because of in silico predictions and proximity to the known I157T FHA variant, which impairs BRCA1, p53, and CDC25 binding, thus potentially promoting tumorigenesis ( Li et al 2002 ). Notably, CHEK2 I157T has been identified as a risk factor for the development of MDS and ET in Polish populations ( Janiszewska et al 2012 ; Janiszewska et al 2018 ). Recently, it was also shown to increase the risk of myeloproliferative neoplasms by promoting self-renewal of HSCs ( Bao et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found a germline variant of unknown significance (VUS) in the checkpoint kinase 2 ( CHEK2 ) tumor-suppressor gene affecting a critical protein domain. CHEK2 is a cancer susceptibility gene that has been associated with MDS ( Janiszewska et al 2018 ). We performed functional validation on this mutant CHK2 protein and demonstrated impaired binding to downstream BRCA1, suggesting this variant may be cancer-predisposing.…”

Section: Introductionmentioning

confidence: 99%