Low-level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer.

Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare.

VhH anti-thrombomodulin clone 1 inhibits TAFI activation and enhances fibrinolysis in human whole blood under flow.

Background: Thrombomodulin on endothelial cells can form a complex with thrombin. This complex has both anticoagulant properties, by activating protein C, and clot-protective properties, by activating thrombin-activatable fibrinolysis inhibitor (TAFI). Activated TAFI (TAFIa) inhibits plasmin-mediated fibrinolysis.

Imaging-based Machine-learning Models to Predict Clinical Outcomes and Identify Biomarkers in Pancreatic Cancer: A Scoping Review.

Objective: To perform a scoping review of imaging-based machine-learning models to predict clinical outcomes and identify biomarkers in patients with PDAC.

Summary Of Background Data: Patients with PDAC could benefit from better selection for systemic and surgical therapy. Imaging-based machine-learning models may improve treatment selection.

Absence of menstruation in female athletes: why they do not seek help.

Background: It is known that amenorrhea is highly prevalent among female athletes. However, a large percentage of them do not seek help if this complaint occurs. We performed this study to gain more insight into the reasons why female athletes do not seek help when experiencing amenorrhea and how care for these women could be improved.

Thrombotic Events in COVID-19 Are Associated With a Lower Use of Prophylactic Anticoagulation Before Hospitalization and Followed by Decreases in Platelet Reactivity.

Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE). To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality. Seventy nine hospitalized COVID-19 patients were enrolled in this retrospective cohort study and provided blood samples in which platelet reactivity in response to stimulation with ADP and TRAP-6 was determined using flow cytometry.

A randomized experimental study to test the effects of discussing uncertainty during cancer genetic counseling: different strategies, different outcomes?

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing.

Association of and gene variation with energy restriction induced adaptations in resting energy expenditure and physical activity.

Background: Energy restriction induces adaptations in resting energy expenditure (REE) and physical activity; inter-individual variability could be ascribed to genetic predisposition.The aim was to examine if changes in REE and physical activity as a result of weight loss were affected by candidate single nucleotide polymorphisms (SNPs).

Methods: 148 subjects (39 men, 109 women), mean ± SD age: 41 ± 9 year; body mass index (BMI): 31.

Three-step site-directed mutagenesis screen identifies pathogenic variants associated with Lynch syndrome.

Background: Inactivating mutations in the MLH1 DNA mismatch repair (MMR) gene underlie 42% of Lynch syndrome (LS) cases. LS is a cancer predisposition causing early onset colorectal and endometrial cancer. Nonsense and frameshift alterations unambiguously cause LS.

'We don't know for sure': discussion of uncertainty concerning multigene panel testing during initial cancer genetic consultations.

Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling.

A head-to-head comparison of conjugation methods for VHHs: Random maleimide-thiol coupling versus controlled click chemistry.

Targeted delivery of therapeutics is an attractive strategy for vascular diseases. Recently, variable domains of heavy-chain-only antibodies (VHHs) have gained momentum as targeting ligands to achieve this. Targeting ligands need adequate conjugation to the preferred delivery platform.

Association of FTO and ADRB2 gene variation with energy restriction induced adaptations in resting energy expenditure and physical activity.

Background: Energy restriction induces adaptations in resting energy expenditure (REE) and physical activity; inter-individual variability could be ascribed to genetic predisposition. The aim was to examine if changes in REE and physical activity as a result of weight loss were affected by candidate single nucleotide polymorphisms (SNPs).

Methods: 148 subjects (39 men, 109 women), mean ± SD age: 41 ± 9 year; body mass index (BMI): 31.

Rapid genetic counseling and testing in newly diagnosed breast cancer: Patients' and health professionals' attitudes, experiences, and evaluation of effects on treatment decision making.

Background: Rapid genetic counseling and testing (RGCT) in newly diagnosed high-risk breast cancer (BC) patients may influence surgical treatment decisions. To successfully integrate RGCT in practice, knowledge of professionals', and patients' attitudes toward RGCT is essential.

Methods: Between 2008 and 2010, we performed a randomized clinical trial evaluating the impact of RGCT.

Risk algorithms that include pathology adjustment for HER2 amplification need to make further downward adjustments in likelihood scores.

To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Purpose: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.

Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia.

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.

Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands.

Recurrent HOXB13 mutations in the Dutch population do not associate with increased breast cancer risk.

The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.

Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?

Objective: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature.

Methods: Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families.

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.

Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry.

Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants.

Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that "oligo targeting" can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS).

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

Background: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.

Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status.

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis.