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Purpose: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families., Methods: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women., Results: We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward., Conclusion: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines., Methods: For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21-74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS 306 ) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined., Findings: Of the women with non-informative PV status, including PRS 306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed., Interpretation: For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age., Funding: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown., Objective: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy., Study Design: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image., Results: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years., Conclusion: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers., Patients and Methods: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression., Results: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1-8.6] and 16.7% [95%CI: 10.8-23.7] in BRCA1 and 4.8% [95%CI: 2.7-7.8] and 16.0% [95%CI: 9.3-24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29-0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29-1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17-0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17-0.68 and HR: 0.22, 95%CI: 0.08-0.62, respectively)., Conclusion: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers., Competing Interests: Declaration of competing interest None. For Fig. A.2, A.3A and A.3B below colour should be used in print., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants., Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis., Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs., Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes., Competing Interests: Conflict of Interest F.J.C. has received consulting fees from Astrazeneca. A.S. has received consulting fees from Pfizer and Astra Zeneca. T.V.O.H. has received honoraria from Pfizer. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS 313 ) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes., Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS 313 and CBC risk., Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS 313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS 313 , HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively., Conclusion: The PRS 313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS 313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making., (© 2021. The Author(s).)

Purpose: Current interpretation guidelines for germline variants in high-risk cancer susceptibility genes consider predicted loss-of-function (LoF) variants, such as nonsense variants and variants in the canonical splice site sequences ofBRCA2, to be associated with high cancer risk. However, some variant alleles produce alternative transcripts that encode (partially) functional protein isoforms leading to possible incorrect risk estimations. For accurate classification of variants it is therefore essential that alternative transcripts are identified and functionally characterized., Methods: We systematically evaluated a large panel of human BRCA2 variants for the production of alternative transcripts and assessed their capacity to exert BRCA2 protein functionality. Evaluated variants included all single-exon deletions, various multiple-exon deletions, intronic variants at the canonical splice donor and acceptor sequences, and variants that previously have been shown to affect messenger RNA (mRNA) splicing in carriers., Results: Multiple alternative transcripts encoding (partially) functional protein isoforms were identified (e.g., ∆[E4-E7], ∆[E6-E7], ∆E[6q39&#95;E8], ∆[E10], ∆[E12], ∆E[12-14]). Expression of these transcripts did attenuate the impact of predicted LoF variants such as the canonical splice site variants c.631+2T>G, c.517-2A>G, c.6842-2A>G, c.6937+1G>A, and nonsense variants c.491T>A, c.581G>A, and c.6901G>T., Conclusion: These results allow refinement of variant interpretation guidelines for BRCA2 by providing insight into the functional consequences of naturally occurring and variant-related alternative splicing events.

Purpose: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias., Methods: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level., Results: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women., Conclusion: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.

Purpose: To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data., Methods: Two sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories., Results: Concordance between the training runs met our prespecified validation criterion. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible., Conclusion: The CIMRA assay accurately predicts pathogenic and benign MMR gene variants. Quantitative combination of assay results with in silico analysis correctly classified the majority of variants. Using this calibration, CIMRA assay results can be integrated into the diagnostic algorithm for MMR gene variants.

Purpose: Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2., Methods: Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants., Results: Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants., Conclusion: The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers.

BRCA1/2 variant analysis in tumor tissue could streamline the referral of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer to genetic counselors and select patients who benefit most from targeted treatment. We investigated the sensitivity of BRCA1/2 variant analysis in formalin-fixed, paraffin-embedded tumor tissue using a combination of next-generation sequencing and copy number variant multiplex ligation-dependent probe amplification. After optimization using a training cohort of known BRCA1/2 mutation carriers, validation was performed in a prospective cohort in which screening of BRCA1/2 tumor DNA and leukocyte germline DNA was performed in parallel. BRCA1 promoter hypermethylation and pedigree analysis were also performed. In the training cohort, 45 of 46 germline BRCA1/2 variants were detected (sensitivity, 98%). In the prospective cohort (n = 62), all six germline variants were identified (sensitivity, 100%), together with five somatic BRCA1/2 variants and eight cases with BRCA1 promoter hypermethylation. In four BRCA1/2 variant-negative patients, surveillance or prophylactic management options were offered on the basis of positive family histories. We conclude that BRCA1/2 formalin-fixed, paraffin-embedded tumor tissue analysis reliably detects BRCA1/2 variants. When taking family history of BRCA1/2 variant-negative patients into account, tumor BRCA1/2 variant screening allows more efficient selection of epithelial ovarian cancer patients for genetic counseling and simultaneously selects patients who benefit most from targeted treatment., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Women seeking counseling because of familial breast cancer occurrence face difficult decisions, such as whether and when to opt for risk-reducing mastectomy (RRM) in case of BRCA1/2 mutation. Only limited research has been done to identify the psychological factors associated with the decision for RRM. This study investigated which psychological factors are related to the intention to choose for RRM., Materials & Methods: A cohort of 486 cancer-unaffected women with a family history of breast cancer completed the following questionnaires prior to genetic counseling: the Cancer Worry Scale, Positive And Negative Affect Scale, Perceived Personal Control Scale, Hospital Anxiety and Depression Scale and State Anxiety Scale and questions regarding socio-demographic characteristics, family history, risk perception and RRM intention. Multivariate logistic regression was used to analyze the relation between psychological factors and women's intention to choose for RRM., Results: Factors associated with RRM intention were high positive affect (OR = 1.86, 95%CI = 1.12-3.08), high negative affect (OR = 2.52, 95%CI = 1.44-4.43), high cancer worry (OR = 1.65, 95%CI = 1.00-2.72), high perceived personal control (OR = 3.58, 95%CI = 2.18-5.89), high risk-perception (OR = 1.85, 95%CI = 1.15-2.95) and having children (OR = 2.06, 95%CI = 1.21-3.50)., Conclusion: Negative and positive affects play an important role in the intention for RRM. Furthermore, perceived personal control over the situation is associated with an intention for RRM. In addition to focusing on accurate risk communication, counseling should pay attention to the influence of perceived control and emotions to facilitate decision-making., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers., Materials and Methods: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level ≥ 3.0 ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate b iopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed., Results: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff ≥ 25; 34%) or 134 (cutoff ≥ 35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥ 25; 28%) or 109 (≥ 35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff ≥ 25) or 43 (cutoff ≥ 35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated., Conclusions: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Previous studies suggest that learning a DNA-test-result has no direct impact on the medical-decisions and psychological well-being of counselees. Their perception, especially their recollections and interpretations of their cancer-risks and heredity, predict and/or mediate this impact. These studies were criticized for their small range of predictors, mediators, outcomes and contextual factors. We studied the short-term impact of DNA-testing with an extended model., Methods: Three months after disclosure of BRCA1/2-test-results, we sent counselees a questionnaire about their perception, medical and psychological outcomes, and medical, familial and psychological contexts. 248 affected women participated; 30 had received pathogenic-mutations, 16 unclassified-variants and 202 uninformative-results., Results: The actually communicated genetic-information and the contextual variables predicted the counselees' perception, but did not directly predict any outcomes. The counselees' perception predicted and/or completely mediated the counselees' medical intentions and behavior, physical and psychological life-changes, stigma, mastery, negativity and cancer-worries. Short-term distress was related to the perception not only of their own risks, but also of their relatives' risks and heredity-likelihood. Effect sizes were medium to large., Conclusions and Implications: The outcomes of DNA-testing were better predicted by the counselees' perception than by the actually given genetic-information. We recommend genetic-counselors to have tailored, interactive dialogues about the counselees' perception., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Genetic counseling may help counselees understand their genetic risk of developing breast/ovarian cancer. However, many studies have shown that their perception of their risks is inaccurate. Information-oriented variables often predicted the level of accuracy, focusing on specific processes of receiving and processing risks. We examined counselee-oriented predictors about how counselees embed cancer risks in their lives. These predictors reflect the personal meaning of genetic risks and are expected to explain/mediate the impact of genetic counseling on risk-perception-accuracy., Method: We analyzed 248 questionnaires of a prospective study, filled in by probands with breast/ovarian cancer and pathogenic mutations, unclassified variants, or uninformative results (n = 30, 16, and 202, respectively). Mediation regression analyses were performed to examine whether counselee predictors mediated/explained the influence of information predictors on the accuracy. Information-oriented predictors regarded presentation format, communicated information, question format, education, pedigree information, cancer experience, and cognitive processes/heuristics. Counselee-oriented predictors regarded their self/personality, life/existence, and need for certainty about DNA test result, heredity, and cancer., Results: Both information-oriented and counselee-oriented variables significantly predicted the accuracy of the counselees' risk perception, with moderate to large effect sizes. Counselee-oriented variables completely mediated/explained the effects of information-oriented variables on the accuracy., Discussion: Counselees seemed to transform objective cancer risks into personally relevant information. Only through this personal meaning of genetic information, information-oriented processes seemed to cause inaccurate perceptions. Genetic counselors are suggested to focus communication on these personal processes.

Background: Unclassified variant and uninformative BRCA1/2 results are not only relevant for probands to whom results are disclosed but also for untested relatives. Previous studies have seldom included relatives and have not explained how their lives were influenced by these results. We explored the family communication timeline of genetic counseling: (1) genetic counselors communicate the relatives' cancer risk, (2) probands perceive this risk and (3) communicate this to relatives; (4) relatives perceive this information, and (5) experience an impact on their lives., Methods: We conducted a retrospective descriptive study in 13 probands with an unclassified variant and 5 with an uninformative result, and in, respectively, 27 and 12 of their untested female relatives from moderate cancer risk families. In questionnaires, probands described their perception of the DNA-test result (i.e., recollections and interpretations of cancer risks and heredity likelihood). Relatives described the communication process, their perception, and impact (i.e., medical decisions, distress, quality of life, and life changes). Bootstrap analysis was used to analyze mediation effects., Results: The relatives' own perception strongly predicted breast self-examination, breast/ovarian surveillance or surgery, levels of distress and quality of life, and amount of reported life changes. The extent to which the proband had communicated the DNA-test result in an understandable, direct, reassuring way, predicted the relatives' perception. The actual communicated relatives' cancer risks or the proband's perception did not predict relatives' perception and impact measures. Family characteristics influenced the communication process but not the relatives' perception and outcomes., Discussion: Relatives seem to make poorly informed decisions on the basis of their own perception, which was unrelated to the information that probands had communicated on the basis of the actual communicated result. Therefore, genetic counselors may guide probands in the communication process and may directly inform relatives, if possible.

Purpose: Effective communication of DNA-test results requires a sound terminology. However, the variety of terms in literature for DNA-test results other than pathogenic, may create inconsistencies between professionals, and misunderstanding in patients. Therefore, we conducted a theoretical and empirical analysis of the terms most frequently used in articles between 2002 and 2007 for BRCA 1/2-test results other than pathogenic., Design: We analyzed the content validity of the no-pathogenic DNA-test result-terms by comparing the literal and intended meaning of the terms and by examining their clarity and the inclusion of all relevant information. We analyzed the reliability of the terms by measuring the strength of association between terms and their meanings and the consistency among different authors over time., Results: Two hundred twenty-seven articles with 361 no-pathogenic DNA-test result-terms were found. Only two terms seemed to have acceptable validity: variant of uncertain clinical significance and no-pathogenic-DNA-test-result. Only variant of uncertain clinical significance and true negative were found to be used reliably in the literature., Conclusions: Current DNA nomenclature lacks validity and reliability. Transparent DNA-test result terminology should be developed covering both laboratory findings and clinical meaning.

Purpose: An inconclusive DNA-result for breast cancer may leave women with uncertainty that cannot be relieved. We assessed the influence of beliefs women held about their inconclusive DNA-result on psychological well-being and whether women had been able to put the period of DNA testing behind them., Methods: In total, 215 women completed a baseline and a follow-up questionnaire 2.5 till 7 years after DNA test disclosure. Within the group of 147 women who received an inconclusive result (either a personal result or the result of an affected family member) multiple regression analyses were applied to investigate the relevance of women's personal beliefs., Results: Personal beliefs and ambivalence about an inconclusive DNA-result were associated with cancer-related worry and distress (P < 0.05). Moreover, these beliefs seemed to be an especially strong predictor of whether women had been able to leave the period of DNA testing behind them, even after controlling for all measures of psychological distress (P < 0.001)., Discussion: Psychological distress measures may provide an important but incomplete picture of how women make sense of an inconclusive DNA-result. These findings underscore the importance of discussing counselees' beliefs and expectations openly to enhance well-being and adaptation on the long term.

Purpose: To describe patient, tumor, and family histories of cancer in a hospital-based cohort of patients with ovarian cancer and to identify the predictive value of these characteristics for (non)carrying a BRCA1 or BRCA2 mutation., Methods: Women diagnosed with invasive ovarian cancer between 1999 and 2003 in the west region of The Netherlands and unselected for age at diagnosis or cancer family history were included. Information was gathered on patient and tumor characteristics; p53; HER-2/neu, and KI-67 protein-expression; BRCA1/2 mutations; and family histories of cancer. Prediction tests were constructed using multivariate analyses., Results: Our study included 85 women (mean age at diagnosis, 57.6 years; standard deviation, 11.0 years). Six of these women had been previously or concurrently diagnosed with another tumor. Of the ovarian cancers, 41 (48.2%) were in an early stage (FIGO I or II). Five pathogenic mutations (6.1%) and six unclassified variants (7.3%) were identified in BRCA1/2; when the total sensitivity of the mutation scanning was taken into account, it was estimated to reflect seven pathogenic mutations (8.5%) and eight unclassified variants (9.8%). Sixty-nine women (81.2%) had at least one relative with cancer. A personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer were found to predict the presence of pathogenic mutations., Conclusion: As the combination of a personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer had good predictive value for the presence of a pathogenic BRCA1/2 mutation, the presented prediction test is a useful instrument to identify those women eligible for DNA testing.

Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation., Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before test result disclosure. Hereditary cancer distress, worry and cancer risk perception were assessed before, 1 week after, and 6 months after disclosure., Results: Individuals from BRCA1/2 and HNPCC mutation families did not differ with regard to the number of experiences with cancer in relatives, grief symptoms, the course of cancer distress, worry and risk perception through time and most illness perceptions, coping responses and family characteristics. Individuals from BRCA1/2 families perceived hereditary cancer as more serious. They reported more frequently a passive coping style, cancer worry and a less open communication with their partner and children., Conclusion: Besides subtle differences, psychological mechanisms may be mainly identical in individuals opting for BRCA1/2 and HNPCC susceptibility testing., Practice Implications: Based on our findings, using a similar counseling approach for individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing is justified. In this approach, attention should be directed more to individual aspects than to the type of disorder.

Background: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility., Patients and Methods: Cancer-related distress, worry and risk perception were assessed in 271 applicants for genetic testing of an identified mutation in BRCA1/2 (BReast CAncer) or a HNPCC (Hereditary Nonpolyposis Colorectal Cancer) related gene before, one week after, and six months after genetic test disclosure. The course of distress and risk perception were compared between individuals having witnessed parental cancer or loss due to cancer in childhood, adolescence, adulthood and having unaffected parents., Results: Individuals with parental cancer in childhood (under age 13) reported the highest level of cancer related distress, worry and risk perception. Women having their mother affected by breast cancer in puberty (aged 10-13 years) perceived higher breast cancer risks than women with an affected mother in adulthood or without an affected mother. Individuals with an affected parent perceived cancer risks as higher than individuals without an affected parent, but were not more distressed., Conclusions: Experience of parental cancer in childhood is a risk factor for psychological distress during the genetic testing process.

Purpose: To test the "false-reassurance hypothesis," which suggests that women who receive an uninformative BRCA1/2 test result may incorrectly conclude that they no longer have an elevated risk, with possible harmful consequences for adherence to breast surveillance guidelines., Methods: A prospective questionnaire design was used to compare 183 women with an uninformative BRCA test result (94 affected and 89 unaffected) with 41 proven BRCA mutation-carriers and 49 true negatives before and after BRCA1/2 test disclosure., Results: After DNA-test disclosure, test applicants differed from each other with regard to their perception of the likelihood of carrying a deleterious gene (P < 0.0001). The BRCA mutation carriers reported the highest perceived likelihood and the true negatives reported the lowest. Compared to the predisclosure measures, women who received an uninformative DNA test result reported a lower perceived risk after disclosure (P < 0.0001), suggesting a relatively high level of reassurance because of the test result. However, after DNA-test disclosure, only 12 women concluded that the risk of carrying a mutation was nonexistent, and perceived likelihood was significantly associated with the pedigree-based risk assessment (P = 0.0001). Moreover, despite the significant decrease in perceived likelihood for uninformative women, intention to obtain mammograms did not change (P = 0.71); it remained at the same almost optimal level as for BRCA mutation carriers., Conclusion: No support was found for the suggestion that the nature of uninformative test results is often misunderstood. Moreover, an uninformative test result did not affect the positive mammography intentions of both affected and unaffected women.

Recent advances in the identification of genetic abnormalities associated with certain types of cancer have stimulated the development of screening and counseling programs for hereditary and familial forms of cancer. In 1995, such a program was established in a collaboration between three familial cancer clinics in Amsterdam. Given the potential impact of genetic screening and counseling on the psychosocial health of participants, it was considered essential that the program be evaluated from its inception to determine the participants' satisfaction with the services provided. A pilot study was initiated in which individuals who received genetic counseling for cancer were asked to provide feedback on the perceived quality of the services provided, and to identify areas in which additional services may be required. Preliminary results based on 36 counseled individuals indicated generally high levels of satisfaction with the care provided by the clinical geneticist and with the procedures at the familial cancer clinics. Several areas were identified that deserve additional attention: (1) the role of the family doctor in the genetic counseling; (2) communication of information regarding the possible impact of genetic counseling and testing on daily life; (3) communication between the clinical geneticist and other health care workers, and (4) psychosocial support during and after the process of genetic counseling.