Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies

Aloraifi, Fatima; McCartan, Damian; McDevitt, Trudi; Green, Andrew J.; Bracken, Adrian P.; Geraghty, James

doi:10.1016/j.cancergen.2015.06.001

Cited by 30 publications

(18 citation statements)

References 52 publications

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“…In our sample of 5589 BC index cases, we confirmed that PTVs in the ATM , CDH1 , CHEK2 , PALB2, and TP53 genes increase BC risk. The ORs for the most frequently mutated genes ( ATM (OR: 3.63, 95% CI 2.67–4.94), CHEK2 (OR: 2.93, 95% CI 2.29–3.75), and PALB2 (OR: 9.53, 95% CI 6.25–14.51) are compatible with published data, according to a meta‐analysis focusing on PTVs . In this meta‐analysis, an aggregated OR of 3.20 (95% CI 2.04–5.04; analysis of 4266 cases and 5566 controls) was calculated for ATM , an aggregated OR of 3.25 (95% CI 2.55–4.13, analysis of 7263 cases and 13,785 controls) was calculated for CHEK2 , and an aggregated OR of 21.40 (95% CI 10.10–45.32, analysis of 5862 cases and 17,453 controls) was calculated for PALB2 .…”

Section: Discussionsupporting

confidence: 86%

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

et al. 2018

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The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM,CDH1,CHEK2,NBN,PALB2,RAD51C,RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2,PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.

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Section: Discussionsupporting

confidence: 86%

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

et al. 2018

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“…Data on ATM, NBS1 (NBN), BRIP1, BLM, etc. are less comprehensive, but nevertheless these genes may also be regarded as substantial contributors to breast cancer risk [8,9,26,[127][128][129][130][131].…”

Section: Breast Cancermentioning

confidence: 98%

“…Consideration of yet unstudied ethnicities may facilitate the discovery of new medically relevant genes. For example, breast cancer predisposing role of NBS1 (NBN) was initially discovered in Polish patients, which are characterized by increased frequency of NBS1 mutations, and later validated in other studies [127,128,131,152].…”

Section: Article In Pressmentioning

confidence: 99%

Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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“…Screening studies, therefore, play a crucial role in selecting significantly important parameters but also being eligible to remove insignificant variables [28]. One of the most useful features of screening studies is to limit the actual runs, therefore leading to a noticeable decrease in performance-related costs while the experiments still obtain a high confidence level under standardized tests [29][30][31]. Indeed, these screening studies (e.g., minimum-run resolution IV) are first conducted to shorten the number of factors and the optimization models (e.g., response surface methodology (RSM)) can then be applied for other factors.…”

Section: Introductionmentioning

confidence: 99%

Combined Minimum-Run Resolution IV and Central Composite Design for Optimized Removal of the Tetracycline Drug Over Metal–Organic Framework-Templated Porous Carbon

Tran

Nguyen

Le³

et al. 2019

Molecules

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In this study, a minimum-run resolution IV and central composite design have been developed to optimize tetracycline removal efficiency over mesoporous carbon derived from the metal-organic framework MIL-53 (Fe) as a self-sacrificial template. Firstly, minimum-run resolution IV, powered by the Design–Expert program, was used as an efficient and reliable screening study for investigating a set of seven factors, these were: tetracycline concentration (A: 5–15 mg/g), dose of mesoporous carbons (MPC) (B: 0.05–0.15 g/L), initial pH level (C: 2–10), contact time (D: 1–3 h), temperature (E: 20–40 °C), shaking speed (F: 150–250 rpm), and Na+ ionic strength (G: 10–90 mM) at both low (−1) and high (+1) levels, for investigation of the data ranges. The 20-trial model was analyzed and assessed by Analysis of Variance (ANOVA) data, and diagnostic plots (e.g., the Pareto chart, and half-normal and normal probability plots). Based on minimum-run resolution IV, three factors, including tetracycline concentration (A), dose of MPC (B), and initial pH (C), were selected to carry out the optimization study using a central composite design. The proposed quadratic model was found to be statistically significant at the 95% confidence level due to a low P-value (<0.05), high R2 (0.9078), and the AP ratio (11.4), along with an abundance of diagnostic plots (3D response surfaces, Cook’s distance, Box-Cox, DFFITS, Leverage versus run, residuals versus runs, and actual versus predicted). Under response surface methodology-optimized conditions (e.g., tetracycline concentration of 1.9 mg/g, MPC dose of 0.15 g/L, and pH level of 3.9), the highest tetracycline removal efficiency via confirmation tests reached up to 98.0%–99.7%. Also, kinetic intraparticle diffusion and isotherm models were systematically studied to interpret how tetracycline molecules were absorbed on an MPC structure. In particular, the adsorption mechanisms including “electrostatic attraction” and “π–π interaction” were proposed.

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Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies

Cited by 30 publications

References 52 publications

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Identification of novel hereditary cancer genes by whole exome sequencing

Combined Minimum-Run Resolution IV and Central Composite Design for Optimized Removal of the Tetracycline Drug Over Metal–Organic Framework-Templated Porous Carbon

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