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Background: Pathogenic variants in the CDKN2A 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 CDKN2A 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. Results: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%). Conclusions: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk. [ABSTRACT FROM AUTHOR]

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. The queries arise especially if syndrome causing mutations are also known to occur in tumors. It needs insight in the mechanisms to understand and explain differences of tumor occurrence, and to offer optimal care to individuals with syndromes. Here we provide a short overview of the major mechanisms of the control for tumor occurrences in malformation syndromes. [ABSTRACT FROM AUTHOR]

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. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0–T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = − 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = −0.55), level of deliberation (ES = − 0.50), and realistic expectations (ES = − 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing. [ABSTRACT FROM AUTHOR]

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. Format preferences and risk understanding (accuracy) were assessed at 2-week follow-up by a questionnaire, completed by 279/326 women. Results: The most preferred risk communication formats were numbers combined with verbal descriptions (37%) and numbers only (26%). Of the numerical formats, most (55%) women preferred percentages. The majority (73%) preferred to be informed about both lifetime and 10-year age-related risk. Women who had received a graphical display were more likely to choose a graphical display as their preferred format. There was no significant effect between the intervention groups with regard to risk accuracy. Overall, women given risk estimates in their preferred format had a slightly better understanding of risk. Conclusion: The results suggest that the accuracy of breast cancer risk estimation is slightly better for women who had received this information in their preferred format, but the risk format used had no effect on women's risk accuracy. To meet the most frequent preference, counselors should consider providing a time frame of reference (eg, risk in the next 10 years) in a numerical format, in addition to lifetime risk. [ABSTRACT FROM AUTHOR]

Background The currently known breast cancerassociated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNPbased polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8% of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families. [ABSTRACT FROM AUTHOR]

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. T0–T1 and T0–T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self‐efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision‐making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling. [ABSTRACT FROM AUTHOR]

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. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management. [ABSTRACT FROM AUTHOR]

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. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision. [ABSTRACT FROM AUTHOR]

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 correlation between RRSO and cholesterol profile was assessed with logistic regression. Furthermore, subgroup analyses were performed to explore a possible effect of age at and time since RRSO. At a median time of 5.9 years (range 2.3-25.2) after surgery, RRSO was associated with low (< 60 mg/dl) HDL-cholesterol (OR 9.74, 95% CI 5.19-18.26) and high (≥ 160 mg/dl) non-HDL-cholesterol (OR 1.85, 95% CI 1.21-2.82) when adjusting for body mass index, hormone therapy, participation on sports and previous chemotherapy. The observed association was not dependent on age or time since RRSO. The RRSO group had less smokers (19.3 vs. 25.8%) and more participation on sports (45.4 vs. 22.0%). Our results suggest that RRSO is associated with a more atherogenic cholesterol profile, despite a lower prevalence of smoking and higher prevalence of participation on sports as compared to controls. This observation can be useful for physicians involved in the counselling and follow-up of women having RRSO. [ABSTRACT FROM AUTHOR]

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. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.Results: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.Conclusion: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers. Premenopausal RRSO is hypothesized to increase fracture risk more than natural menopause. Elevated bone turnover markers (BTMs) might predict fracture risk. We investigated BTM levels after RRSO and aimed to identify clinical characteristics associated with elevated BTMs. Methods: Osteocalcin (OC), procollagen type I N-terminal peptide (PINP) and serum C-telopeptide of type I collagen (sCTx) were measured in 210 women ≥ 2 years after RRSO before age 53. BTM Z-scores were calculated using an existing reference cohort of age-matched women. Clinical characteristics were assessed by questionnaire. Results: BTMs after RRSO were higher than age-matched reference values: median Z-scores OC 0.11, p = 0.003; PINP 0.84, p < 0.001; sCTx 0.53, p < 0.001 (compared to Z = 0). After excluding women with recent fractures or BTM interfering medication, Z-scores increased to 0.34, 1.14 and 0.88, respectively. Z-scores for OC and PINP were inversely correlated to age at RRSO. No correlation was found with fracture incidence or history of breast cancer. Conclusions: Five years after RRSO, BTMs were higher than age-matched reference values. Since elevated BTMs might predict higher fracture risk, prospective studies are required to evaluate the clinical implications of this finding. [ABSTRACT FROM AUTHOR]

Study Question: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels?Summary Answer: BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders.What Is Known Already: It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%).Participants/materials, Setting, Method: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels.Main Results and the Role Of Chance: Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76).Limitations, Reasons For Caution: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis.Wider Implications Of the Findings: Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care.Study Funding/competing Interests: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work.Trial Registration Number: NTR no. 4324. [ABSTRACT FROM AUTHOR]

Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1 matched controls. Controls, unscreened if<50 years, and screened with biennial mammography if ≥50 years, were matched on risk category ( BRCA1, BRCA2, familial risk), year and age of diagnosis. Of 2,308 MRISC participants, breast cancer was detected in 93 (97 breast cancers), who received MRI <2 years before breast cancer diagnosis; 33 BRCA1 mutation carriers, 18 BRCA2 mutation carriers, and 42 with familial risk. MRISC patients had smaller (87% vs. 52%

Annual MRI and mammography is recommended for BRCA1/ 2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as 'unfavourable.' Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79-9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening ( p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60-year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile. [ABSTRACT FROM AUTHOR]

Background BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. Methods We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. Results The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (pheterogeneity = 0.0006) and stronger family histories of breast cancer (pheterogeneity<0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. Conclusions BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers. [ABSTRACT FROM AUTHOR]

Background To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear. Methods We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided. Results Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (€93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (€102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (€41 390) per LYG with mammography only. Conclusions Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories. [ABSTRACT FROM AUTHOR]

Women from high-risk families consider preventive measures for breast cancer including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected relatives is predictive for age at diagnosis. We analyzed the age of breast cancer detection of 1,304 first- and second-degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within- and between-family variance in the relative's age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK-MARIBS study. Mean age at diagnosis in the relatives varied between families; 95% range of mean family ages was 35-55 in BRCA1-, 41-57 in BRCA2- and 44-60 in high-risk families. In all, 14% of the variance in age at diagnosis, in BRCA1 even 23%, was explained by family history, 7% by risk group. Determining start of screening based on the model and on risk-group gave similar results in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and the United Kingdom data sets. Age at breast cancer diagnosis is partly dependent on family history which may assist planning starting age for preventive measures. [ABSTRACT FROM AUTHOR]

Background: Inadequate understanding of risk among counselees is a common problem in familial cancer clinics. It has been suggested that graphical displays can help counselees understand cancer risks and subsequent decision-making. We evaluated the effects of a graphical presentation in addition to a frequency format on counselees' understanding, psychological well-being, and preventive intentions. Design: Multicenter controlled trial. Setting: Three familial cancer clinics in the Netherlands. Methods: Participants: Unaffected women with a breast cancer family history (first-time attendees). Intervention: Immediately after standard genetic counseling, an additional consultation by a trained risk counselor took place where women were presented with their lifetime breast cancer risk in frequency format (X out of 100) (n = 63) or frequency format plus graphical display (10 × 10 human icons) (n = 91). Main outcome measures: understanding of risk (risk accuracy, risk perception), psychological well-being, and intentions regarding cancer prevention. Measurements were assessed using questionnaires at baseline, 2-week and 6-month follow-up. Results: Baseline participant characteristics did not differ between the two groups. In both groups there was an increase in women's risk accuracy from baseline to follow-up. No significant differences were found between women who received the frequency format and those who received an additional graphical display in terms of understanding, psychological well-being and intentions regarding cancer prevention. The groups did not differ in their evaluation of the process of counseling. Conclusion: Women's personal risk estimation accuracy was generally high at baseline and the results suggest that an additional graphical display does not lead to a significant benefit in terms of increasing understanding of risk, psychological well-being and preventive intentions. [ABSTRACT FROM AUTHOR]

Background Many cancer-patients undergo DNA testing in the BRCA1/2 genes to receive information about the likelihood that cancer is heritable. Previous nonsystematic studies suggested that DNA testing often does not fulfill the counselees' needs for certainty. We explored the balance between the counselees' need for certainty and perceived certainty (NfC-PC, i.e., level of fulfillment of NfC) regarding the specific domains of DNA test result, heredity and cancer. We also examined relationships of NfC-PC with coping styles and distress. Method Before disclosure of BRCA1/2 test results for hereditary breast/ovarian cancer (T1), questionnaires were filled in by 467 cancer-patients. Another questionnaire (T2) was filled in after disclosure of pathogenic mutation results ( n = 30), uninformative results ( n = 202) or unclassified-variants ( n = 16). Results Before and after DNA test result disclosure, overall 58-94% of all counselees experienced unfulfilled NfC regarding the DNA test result, heredity and cancer. Compared with T1, the communication of pathogenic mutations (T2) caused more fulfillment of the NfC about the DNA test result, but less about cancer and heredity ( p < .01). Compared with T1, unclassified variants (T2) did not significantly change the extent of fulfillment of all counselees' needs for certainty (NfC > PC). Compared with T1, uninformative results (T2) caused more fulfillments of all needs than before disclosure ( p < 0.01). Counselees differentiated NfC and PC between the domains of DNA-test result, heredity and cancer ( p < 0.01). The unfulfilled needs for certainty (NfC-PC) were uncorrelated with cognitive understanding of the DNA test result. Conclusion The counselees' NfC needs more attention in research and practice, for example, when the potential uncertainties of testing are discussed. The counselees' NfC may be assessed and used in tailored, mutual communication of DNA test results. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Several studies have shown that counselees do not experience psychopathological levels of distress after DNA test result disclosure. However, it has not systematically been studied whether the absence of psychopathology also means that counselees do not want to receive help. Their self-reported request for help may be related not only with psychopathology/distress but also with other psychological needs (e.g., surgery decisions), genetics-specific needs (e.g., feeling vulnerable/stigmatized), and existential concerns (e.g., meaning in life). Methods Questionnaires were filled in by Dutch cancer patients, before and after disclosure of BRCA1/2 test results for hereditary breast/ovarian cancer: pathogenic mutation results ( n = 30), uninformative results ( n = 202), or unclassified variants ( n = 16). Newly developed questions measured request for help, psychopathology was estimated with factor analyses on distress/psychopathology instruments, and several validated questionnaires measured other needs/concerns. Results One-third of all counselees who reported a request for psychological help had actually received help. The level of psychopathology correlated between 0.34 and 0.44 with this self-reported need-for-help. Other needs, genetics-specific distress, and existential concerns correlated strongly/moderately with the counselees' self-reported need-for-help. Examples of other needs were intention to undergo surgery, inaccuracy of their interpretation, the impact of cancer, and family communication difficulties. Genetics-specific distress was for instance feeling vulnerable to develop cancer, stigma, and lack of mastery. Existential concerns were, among others, lack of purpose in life, low self-acceptance, and an unfulfilled wish for certainty. Conclusions The request for help is related to multiple factors. Referral to psychosocial professionals may be improved by not only discussing psychopathology during genetic-counseling sessions but also by other needs and existential concerns. Questions about other needs and existential issues may be added to psychological screening instruments. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: It has been hypothesized that the Outcomes of DNA testing (O) are better predicted and/or mediated by the counselees' Perception P) than by the actually communicated genetic Information (I). In this study, we aimed at quantifying the effect that perception has in genetic counseling for hereditary breast/ovarian cancer. Methods: Two hundred and four women, who had previously been tested for BRCA1/2, participated in a retrospective questionnaire study; 93% had cancer. Communicated Information (I) consisted of cancer risks and BRCA1/2 test result category: unclassified variant ( n = 76), uninformative ( n = 76), pathogenic mutation ( n = 51). Four perception variables (P) were included: the counselees' recollections and interpretations of both the cancer risks and the likelihood that the cancer in their family is heritable. The Outcome variables (O) included life changes, counselees' medical decisions, BRCA-related self-concept, current psychological well-being, and quality-of-life. Bootstrap mediation analyses determined whether relationships were direct (I→O or P→O) or indirect through the mediation of perception (I→P→O). Results: The actually communicated pathogenic mutation and uninformative result directly predicted medical decisions (I→O), i.e. intended and performed surgery of breasts/ovaries. All other outcomes were only directly predicted by the counselees' perception (recollection and interpretation) of their cancer risks and heredity likelihood (P→O), or this perception mediated the outcome (I→P→O). However, this perception was significantly different from the actually communicated cancer risks (I→P). Unclassified variants were inaccurately perceived (mostly overestimated); this misperception predicted both psychological outcomes and radical medical decisions. Discussion: Genetic counselors need to explicitly address the counselee's interpretations and intended medical decisions. In case of misinterpretations, additional counseling might be offered. Communication of unclassified variants needs special attention given the pitfall of overestimation of risk. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test. The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density. Methods/Design: This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000). Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value ofboth screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor. Discussion: Personalized breast cancer screening might optimize mortality reduction with less over diagnosis.Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition. Trial registration: Netherland Trial Register NTR2789 [ABSTRACT FROM AUTHOR]

Background: Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women.Methods: A systematic search was conducted for articles addressing breast cancer, mammography screening, radiation and high-risk women. Effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR).Results: Of 127 articles found, 7 were selected for the meta-analysis. Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) or a mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0) was significantly associated with a higher radiation-induced breast cancer risk.Conclusion: Low-dose radiation increases breast cancer risk among high-risk women. When using low-dose radiation among high-risk women, a careful approach is needed, by means of reducing repeated exposure, avoidance of exposure at a younger age and using non-ionising screening techniques. [ABSTRACT FROM AUTHOR]

Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12-Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1-9, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan–Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a ‘wait and scan’ policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients. [ABSTRACT FROM AUTHOR]

Rapid and reliable identification of deleterious changes in the breast cancer genes BRCA1 and BRCA2 has become one of the major issues in most DNA services laboratories. To rapidly detect all possible changes within the coding and splice site determining sequences of the breast cancer genes, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. All exons of both genes are covered by the DGGE scan, comprising 120 amplicons. We use a semiautomated approach, amplifying all individual amplicons with the same PCR program, after which the amplicons are pooled. DGGE is performed using three slightly different gel conditions. Validation was performed using DNA samples with known sequence variants in 107 of the 120 amplicons; all variants were detected. This DGGE mutation scanning, in combination with a PCR test for two Dutch founder deletions in BRCA1 was then applied in 431 families in which 52 deleterious changes and 70 unclassified variants were found. Fifteen unclassified variants were not reported before. The system was easily adopted by five other laboratories, where in another 3,593 families both exons 11 were analyzed by the protein truncation test (PTT) and the remaining exons by DGGE. In total, a deleterious change (nonsense, frameshift, splice-site mutation, or large deletion) was found in 661 families (16.4%), 462 in BRCA1 (11.5%), 197 in BRCA2 (4.9%), and in two index cases a deleterious change in both BRCA1 and BRCA2 was identified. Eleven deleterious changes in BRCA1 and 36 in BRCA2 had not been reported before. In conclusion, this DGGE mutation screening method for BRCA1 and BRCA2 is proven to be highly sensitive and is easy to adopt, which makes screening of large numbers of patients feasible. The results of screening of BRCA1 and BRCA2 in more than 4,000 families present a valuable overview of mutations in the Dutch population. Hum Mutat 27(7), 654-666, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories. [ABSTRACT FROM AUTHOR]

Background Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. Methods The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms. Results The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls. Conclusions Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer. [ABSTRACT FROM AUTHOR]

Background: Inadequate understanding of risk among counselees is a common problem in familial cancer clinics. It has been suggested that graphical displays can help counselees understand cancer risks and subsequent decision-making. We evaluated the effects of a graphical presentation in addition to a frequency format on counselees' understanding, psychological well-being, and preventive intentions.Design: Multicenter controlled trial.Setting: Three familial cancer clinics in the Netherlands.Methods: Participants: Unaffected women with a breast cancer family history (first-time attendees).Intervention: Immediately after standard genetic counseling, an additional consultation by a trained risk counselor took place where women were presented with their lifetime breast cancer risk in frequency format (X out of 100) (n = 63) or frequency format plus graphical display (10 × 10 human icons) (n = 91).Main Outcome Measures: understanding of risk (risk accuracy, risk perception), psychological well-being, and intentions regarding cancer prevention. Measurements were assessed using questionnaires at baseline, 2-week and 6-month follow-up.Results: Baseline participant characteristics did not differ between the two groups. In both groups there was an increase in women's risk accuracy from baseline to follow-up. No significant differences were found between women who received the frequency format and those who received an additional graphical display in terms of understanding, psychological well-being and intentions regarding cancer prevention. The groups did not differ in their evaluation of the process of counseling.Conclusion: Women's personal risk estimation accuracy was generally high at baseline and the results suggest that an additional graphical display does not lead to a significant benefit in terms of increasing understanding of risk, psychological well-being and preventive intentions.Trial Registration: Current Controlled Trials http://ISRCTN14566836. [ABSTRACT FROM AUTHOR]