Pathogenic Variants in <i>CHEK2</i> Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer

Greville‐Heygate, Stephanie; Maishman, Tom; Tapper, William; Cutress, Ramsey I.; Copson, Ellen; Dunning, Alison M.; Haywood, Linda; Jones, Louise; Eccles, Diana

doi:10.1200/po.19.00178

Cited by 19 publications

(21 citation statements)

References 28 publications

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“…We also observed an association with ductal carcinoma diagnosis, which has been also demonstrated by other researchers [ 20 ], along with an increased rate, i.e., 19.2%, of contralateral breast cancer diagnoses. This is in concordance with other reports, where rates have been reported to range between 9.4–21% [ 26 , 27 , 28 ]. Furthermore, in our series, hormone therapy and/or mastectomy at primary diagnoses seem to have a positive effect on survival of CHEK2 carriers.…”

Section: Discussionsupporting

confidence: 94%

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Apostolou

Dellatola

Papadimitriou

et al. 2021

Cancers

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CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.

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Section: Discussionsupporting

confidence: 94%

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Apostolou

Dellatola

Papadimitriou

et al. 2021

Cancers

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“…A recent study has suggested that patients with invasive breast cancer carrying the c.1100delC mutation are more likely to be obese, though this is not the case for the general population ( Greville-Heygate et al , 2020 ). Thus, when we tested for such an interaction between PCOS, c.1100delC, and obesity using a logit regression model, a P -value of 0.066 for c.1100delC-BMI interaction was obtained (OR 1.04, 95% CI 0.99–1.09).…”

Section: Resultsmentioning

confidence: 99%

“…We tested whether an interaction between c.1100delC mutation, obesity and PCOS could be detected, as such a phenomenon has been identified between the mutation carriers in invasive breast cancer ( Greville-Heygate et al , 2020 ). We fitted a logistic model where PCOS was the outcome, the lead variant genotype and BMI formed the interaction term, and the 10 first genetic PCs along with age were added as covariates.…”

Section: Methodsmentioning

confidence: 99%

Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome

et al. 2021

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STUDY QUESTION Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? SUMMARY ANSWER We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10). WHAT IS KNOWN ALREADY PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects. STUDY DESIGN, SIZE, DURATION A population-based case–control GWAS was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case–control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts. MAIN RESULTS AND THE ROLE OF CHANCE Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10−8, odds ratio (OR) = 3.01 [2.02–4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10−16, OR = 1.69 [1.49–1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10−8, OR = 1.16 [1.10–1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10−16, OR = 1.74 [1.5–2.01]) possibly owing to reduced sample size. LARGE SCALE DATA The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903. LIMITATIONS, REASONS FOR CAUTION The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values. WIDER IMPLICATIONS OF THE FINDINGS This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS. STUDY FUNDING/COMPETING INTEREST(S) This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the MATER Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.

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“…and Finnish (0.029) populations, compared to the Non-Finnish, North-Western European population (0.002) according to the gnomAD database [55]. The enrichment of the alleles likely allowed us to detect the associations with PCOS in the Finnish and Estonian populations, whereas in populations with lower minor allele frequencies, much larger study populations would need to be used.…”

Section: Discussionmentioning

confidence: 99%

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Tyrmi

Arffman

Pujol-Gualdo

et al. 2021

Preprint

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Background: Polycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe - Finnish and Estonian - to provide a basis for a new understanding of the genetic determinants of PCOS. Methods and Findings: We conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts. In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 x 10-8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 x 10-16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 x 10-8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16. Conclusions: We identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.

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Pathogenic Variants in CHEK2 Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer

Cited by 19 publications

References 28 publications

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

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