PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD.

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Background: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

Methods: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes.

Genetic control of tumor development in malformation syndromes.

One of the questions that arises frequently when caring for an individual with a malformation syndrome, is whether some form of tumor surveillance is indicated. In some syndromes there is a highly variable increased risk to develop tumors, while in others this is not the case. The risks can be hard to predict and difficult to explain to affected individuals and their families, and often also to caregivers.

Reproductive decision-making in the context of hereditary cancer: the effects of an online decision aid on informed decision-making.

Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018.

Cost-effectiveness of Breast Cancer Screening With Magnetic Resonance Imaging for Women at Familial Risk.

Importance: For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM 113705; and BRCA2, OMIM 114480) or TP53 (OMIM 151623) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce.

Objective: To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant.

Design, Setting, And Participants: In this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant.

Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic variants.

Background: Pathogenic variants in the gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants.

Methods: Using the Dutch national familial melanoma database, we identified all families with a pathogenic variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families.

Do Preferred Risk Formats Lead to Better Understanding? A Multicenter Controlled Trial on Communicating Familial Breast Cancer Risks Using Different Risk Formats.

Purpose: Counselees' preferences are considered important for the choice of risk communication format and for improving patient-centered care. We here report on counselees' preferences for how risks are presented in familial breast cancer counseling and the impact of this preferred format on their understanding of risk.

Patients And Methods: As part of a practice-based randomized controlled trial, 326 unaffected women with a family history of breast cancer received their lifetime risk in one of five presentation formats after standard genetic counseling in three Dutch familial cancer clinics: 1) in percentages, 2) in frequencies ("X out of 100"), 3) in frequencies plus graphical format (10×10 human icons), 4) in frequencies and 10-year age-related risk and 5) in frequencies and 10-year age-related risk plus graphical format.

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

MRI versus mammography for breast cancer screening in women with familial risk (FaMRIsc): a multicentre, randomised, controlled trial.

Background: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.

Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants.

Addition of a 161-SNP polygenic risk score to family history-based risk prediction: impact on clinical management in non- breast cancer families.

Background: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non- high-risk breast cancer families.

Methods: 101 non- high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped.

[Genetic testing in patients with cancer; new developments].

Genetic testing in patients with cancer; new developments About 5% of patients with cancer have a causative germline mutation. When a germline mutation is detected, this may have major implications for treatment and follow-up of the patient, as well as for relatives who are at risk of carrying the mutation. Increasingly, DNA-testing of tumor tissue is being performed to identify potential druggable targets, aiming at personalized medicine.

Should women with a BRCA1/2 mutation aged 60 and older be offered intensified breast cancer screening? - A cost-effectiveness analysis.

Objectives: This study aimed to investigate the cost-effectiveness of intensified breast cancer (BC) screening for women with a BRCA1/2 mutation aged 60-74. Simulated strategies were: (0) annual mammography as reference, (1) alternating annual mammography and MRI for women with dense breasts only; (2) addition of annual MRI for women with dense breasts only; (3) addition of annual MRI for all women.

Materials And Methods: A validated micro-simulation model of invasive BC was updated and validated for interval BC rates and tumor size distribution.

Multiple tumors due to mosaic genome-wide paternal uniparental disomy.

Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith-Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed.

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With or Mutations.

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for and mutation carriers.

Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 and 3525 mutation carriers) and a prospective cohort (2276 and 1610 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.

Online decision support for persons having a genetic predisposition to cancer and their partners during reproductive decision-making.

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements.

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer.

Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers.

Background: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.

Methods: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry.

Cholesterol profile in women with premature menopause after risk reducing salpingo-oophorectomy.

This cross-sectional study aimed to investigate the effect of premenopausal risk reducing salpingo-oophorectomy (RRSO) on the cholesterol profile of women at increased ovarian cancer risk and to assess possible effects of age at and time since RRSO. We included 207 women who underwent RRSO before menopausal age (52 years) attending the family cancer clinic of an academic hospital and 828 age-matched women from a general population cohort (PREVEND). Participants filled out a questionnaire on socio-demographic characteristics, lifestyle and medical history, had anthropometric measurements and provided blood samples for assessment of serum levels of total cholesterol, HDL-cholesterol and non-HDL-cholesterol.

The development of an online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making: a usability and pilot study.

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.

The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position?

This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither).

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.