Publications by authors named "Cora M Aalfs"

72 Publications

A scoping review of practice recommendations for clinicians' communication of uncertainty.

Health Expect 2021 Aug 8;24(4):1025-1043. Epub 2021 Jun 8.

Department of Medical Psychology, Amsterdam UMC, Amsterdam Public Health, Amsterdam, The Netherlands.

Background: Health-care providers increasingly have to discuss uncertainty with patients. Awareness of uncertainty can affect patients variably, depending on how it is communicated. To date, no overview existed for health-care professionals on how to discuss uncertainty.

Objective: To generate an overview of available recommendations on how to communicate uncertainty with patients during clinical encounters.

Search Strategy: A scoping review was conducted. Four databases were searched following the PRISMA-ScR statement. Independent screening by two researchers was performed of titles and abstracts, and subsequently full texts.

Inclusion Criteria: Any (non-)empirical papers were included describing recommendations for any health-care provider on how to orally communicate uncertainty to patients.

Data Extraction: Data on provided recommendations and their characteristics (eg, target group and strength of evidence base) were extracted. Recommendations were narratively synthesized into a comprehensible overview for clinical practice.

Results: Forty-seven publications were included. Recommendations were based on empirical findings in 23 publications. After narrative synthesis, 13 recommendations emerged pertaining to three overarching goals: (a) preparing for the discussion of uncertainty, (b) informing patients about uncertainty and (c) helping patients deal with uncertainty.

Discussion And Conclusions: A variety of recommendations on how to orally communicate uncertainty are available, but most lack an evidence base. More substantial research is needed to assess the effects of the suggested communicative approaches. Until then, health-care providers may use our overview of communication strategies as a toolbox to optimize communication about uncertainty with patients.

Patient Or Public Contribution: Results were presented to stakeholders (physicians) to check and improve their practical applicability.
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http://dx.doi.org/10.1111/hex.13255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369117PMC
August 2021

Effect of a health literacy training program for surgical oncologists and specialized nurses on disparities in referral to breast cancer genetic testing.

Breast 2021 Aug 22;58:80-87. Epub 2021 Apr 22.

Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Background: There is an underuse of genetic testing in breast cancer patients with a lower level of education, limited health literacy or a migrant background. We aimed to study the effect of a health literacy training program for surgical oncologists and specialized nurses on disparities in referral to genetic testing.

Methods: We conducted a multicenter study in a quasi-experimental pre-post (intervention) design. The intervention consisted of an online module and a group training for surgical oncologists and specialized nurses in three regions in the Netherlands. Six months pre- and 12 months post intervention, clinical geneticists completed a checklist with socio-demographic characteristics including the level of health literacy of each referred patient. We conducted univariate and logistic regression analysis to evaluate the effect of the training program on disparities in referral to genetic testing.

Results: In total, 3179 checklists were completed, of which 1695 were from hospital referrals. No significant differences were found in educational level, level of health literacy and migrant background of patients referred for genetic testing by healthcare professionals working in trained hospitals before (n = 795) and after (n = 409) the intervention. The mean age of patients referred by healthcare professionals from trained hospitals was significantly lower after the intervention (52.0 vs. 49.8, P = 0.003).

Conclusion: The results of our study suggest that the health literacy training program did not decrease disparities in referral to genetic testing. Future research in a more controlled design is needed to better understand how socio-demographic factors influence referral to breast cancer genetic testing and what other factors might contribute.
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http://dx.doi.org/10.1016/j.breast.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105680PMC
August 2021

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

Fam Cancer 2021 Mar 9. Epub 2021 Mar 9.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.
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http://dx.doi.org/10.1007/s10689-021-00237-1DOI Listing
March 2021

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

Eur J Hum Genet 2021 May 12;29(5):789-799. Epub 2021 Jan 12.

Department of Medical Psychology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on counselors' communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees' uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N = 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors' communication of uncertainty (comprehensive vs. the essence) and their response to counselees' uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p = 0.002). Comprehensive information resulted in less perceived steering toward testing (p = 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p = 0.025). Participants seeking information experienced less uncertainty (p = 0.003), and trusted their counselor more (p = 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.
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http://dx.doi.org/10.1038/s41431-020-00799-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110589PMC
May 2021

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

J Community Genet 2021 Jan 2;12(1):101-110. Epub 2020 Sep 2.

Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, the Netherlands.

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.
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http://dx.doi.org/10.1007/s12687-020-00484-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846643PMC
January 2021

Prophylactic total pancreatectomy in individuals at high risk of pancreatic ductal adenocarcinoma (PROPAN): systematic review and shared decision-making programme using decision tables.

United European Gastroenterol J 2020 10 23;8(8):865-877. Epub 2020 Jul 23.

Department of Surgery, University of Amsterdam, Amsterdam, The Netherlands.

Background: Individuals with a very high lifetime risk of developing pancreatic ductal adenocarcinoma; for example, hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm, may wish to discuss prophylactic total pancreatectomy but strategies to do so are lacking.

Objective: To develop a shared decision-making programme for prophylactic total pancreatectomy using decision tables.

Methods: Focus group meetings with patients were used to identify relevant questions. Systematic reviews were performed to answer these questions.

Results: The first tables included hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm. No studies focused on prophylactic total pancreatectomy in these groups. In 52 studies (3570 patients), major morbidity after total pancreatectomy was 25% and 30-day mortality was 6%. After minimally invasive total pancreatectomy (seven studies, 35 patients) this was, respectively, 13% and 0%. Exocrine insufficiency-related symptoms occurred in 33%. Quality of life after total pancreatectomy was slightly lower compared with the general population.

Conclusion: The decision tables can be helpful for discussing prophylactic total pancreatectomy with individuals at high risk of pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1177/2050640620945534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707864PMC
October 2020

Addition of an online, validated family history questionnaire to the Dutch FIT-based screening programme did not improve its diagnostic yield.

Br J Cancer 2020 06 20;122(12):1865-1871. Epub 2020 Apr 20.

Department of Gastroenterology and Hepatology, Cancer Centre Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.

Background: Faecal immunochemical testing (FIT) is suboptimal in detecting advanced neoplasia (AN). To increase the sensitivity and yield of a FIT-based screening programme, FIT could be combined with risk factors for AN. We evaluated the incremental yield of adding a family history questionnaire (FHQ) on colorectal cancer (CRC) and Lynch syndrome-associated tumours to the Dutch FIT-based screening programme.

Methods: Six thousand screen-naive individuals, aged 59-75 years, were invited to complete a FIT (FOB-Gold, cut-off 47 µg Hb/g faeces) and a validated online FHQ. Participants with a positive FIT and/or positive FHQ, confirmed after genetic counselling, were referred for colonoscopy. Yield of detecting AN per 1000 invitees for the combined strategy was compared with the FIT-only strategy.

Results: Of the 5979 invitees, 1952 (32.6%) completed the FIT only, 2379 (39.8%) completed both the FIT and FHQ and 95 (1.6%) completed the FHQ only. Addition of the FHQ to FIT-based screening resulted in one extra case of AN detected after 16 additional colonoscopies, resulting in a yield of 19.6 (95% CI, 16.4-23.5) for the combined strategy versus 19.5 (95% CI, 16.3-23.3) for the FIT-only strategy (p = 1.0).

Conclusions: The addition of an FHQ to one round of FIT screening did not increase the detection of AN compared with FIT only (ClinicalTrials.gov NCT02698462).
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http://dx.doi.org/10.1038/s41416-020-0832-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283285PMC
June 2020

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

Fam Cancer 2020 01 26;19(1):65-76. Epub 2019 Nov 26.

Department of Medical Psychology - Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.

Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors' communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors' uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors' background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don't know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p < 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p < 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees' personal uncertainties and concerns during initial cancer genetic counseling is suboptimal.
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http://dx.doi.org/10.1007/s10689-019-00154-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026220PMC
January 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

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

Br J Cancer 2019 07 19;121(2):180-192. Epub 2019 Jun 19.

Department of Gynaecological Oncology, Chris O'Brien Lifehouse and The University of Sydney, Camperdown, NSW, Australia.

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. Associations were assessed using weighted Cox models.

Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P < 0.05).

Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
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http://dx.doi.org/10.1038/s41416-019-0492-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738050PMC
July 2019

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Hum Mutat 2019 09;40(9):1557-1578

Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
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http://dx.doi.org/10.1002/humu.23818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772163PMC
September 2019

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

J Genet Couns 2019 06 21;28(3):533-542. Epub 2018 Dec 21.

Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1002/jgc4.1056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380023PMC
June 2019

Uncertainty related to multigene panel testing for cancer: a qualitative study on counsellors' and counselees' views.

J Community Genet 2019 Apr 14;10(2):303-312. Epub 2018 Nov 14.

Department of Medical Psychology - Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.

Multigene panel testing is mainly used to improve identification of genetic causes in families with characteristics fitting multiple possible cancer syndromes. This technique may yield uncertainty, for example when variants of unknown significance are identified. This study explores counsellors' and counselees' experiences with uncertainty, and how they discuss uncertainties and decide about multigene panel testing. Six focus groups were conducted including 38 counsellors. Twelve counselees who had received genetic counselling about a multigene panel test were interviewed. The focus group sessions and interviews were audio-recorded and transcribed verbatim. Transcripts were analysed inductively by two independent coders and data were examined to obtain a comprehensive list of themes. Counsellors identified several uncertainties, e.g. finding a variant of unknown significance, or detecting an unsolicited finding. Most difficulty was experienced in deciding what uncertain information to communicate to counselees and how to do so. The extent and manner of providing uncertain information differed between centres and between counsellors. Counsellors attached more value to counselees' preferences in decision making compared to less extended tests. Counselees experienced difficulty in recalling which uncertainties had been discussed during genetic counselling. They primarily reported to have experienced uncertainty about their own and their relatives' risk of developing cancer. Counselees felt they had had a say in the decision. This study showed that counsellors need more guidance on whether and how to convey uncertainty. Undesirable practice variation in the communication of uncertainty may be prevented by determining what information should minimally be discussed to enable informed decision making.
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http://dx.doi.org/10.1007/s12687-018-0393-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435776PMC
April 2019

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

J Natl Cancer Inst 2019 04;111(4):350-364

Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT.

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.
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http://dx.doi.org/10.1093/jnci/djy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449171PMC
April 2019

Uncertainty in consultations about genetic testing for cancer: an explorative observational study.

Patient Educ Couns 2018 12 2;101(12):2083-2089. Epub 2018 Aug 2.

Department of Medical Psychology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Cancer Centre Amsterdam, Amsterdam, The Netherlands.

Objective: Persons seeking cancer genetic counseling mainly aim to obtain information and certainty about their medical situation. However, the information that counselees receive often involves many uncertainties. To develop strategies to enable optimal communication about uncertainties, the spectrum of uncertainty expressed within cancer genetic counseling needs to be established. This study aimed to gain insight into the uncertainties verbally expressed by counselors and counselees.

Methods: Twenty-five consultations were audiotaped, transcribed and qualitatively analyzed. A coding scheme identifying all uncertainties was developed parallel to the coding of the transcripts.

Results: Several uncertainties were identified varying in their source (i.e. the cause of uncertainty) and the issues involved (i.e. the topic to which uncertainty pertained). The main sources of uncertainty were the unpredictability of the future and a lack of knowledge. Counselees also expressed uncertainty related to the amount and complexity of the information. Counselors expressed uncertainties mainly related to scientific issues, whereas counselees' uncertainty mainly related to personal and practical issues.

Conclusion: A wide range of uncertainties was expressed by both groups. Counselors differ from counselees in the degree and types of uncertainty they express.

Practice Implications: Counselors should address scientific uncertainties during genetic counseling to increase awareness and understanding in counselees.
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http://dx.doi.org/10.1016/j.pec.2018.08.002DOI Listing
December 2018

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.

Fam Cancer 2019 01;18(1):137-146

Department of Clinical Genetics, Maastricht University Medical Centre+, Postbox 5800, 6202 AZ, Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1007/s10689-018-0092-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323089PMC
January 2019

How to support cancer genetics counselees in informing at-risk relatives? Lessons from a randomized controlled trial.

Patient Educ Couns 2018 09 8;101(9):1611-1619. Epub 2018 May 8.

Department of Medical Psychology, Academic Medical Centre, University of Amsterdam, The Netherlands. Electronic address:

Objective: In hereditary and familial cancer, counselees are requested to inform their at-risk relatives. We developed an intervention to support counselees in this task.

Methods: A randomized controlled trial was conducted aimed at improving cancer genetic counselees' i) knowledge, ii) motivation to disclose information, and ii) self-efficacy in this regard. Eligible participants were randomized to telephonic counseling (n = 148), or standard care (n = 157) and assessed at baseline, 1 week post-intervention, and 4 months after study enrolment.

Results: No between-group differences were found in participants' knowledge, motivation, and self-efficacy. Knowledge concerning which second-degree relatives to inform was lower compared to first-degree relatives. About 60% of the participants was of the opinion that they needed to inform more relatives than stated in their summary letter and only about 50% were correctly aware of which information to disclose. Of note, at baseline, almost 80% of the participants had already correctly informed their at-risk relatives.

Conclusions: Since, unexpectedly, counselees already informed most of their relatives before the intervention was offered, efficacy of the intervention could not convincingly be determined. Counselees' knowledge about whom to inform about what is suboptimal.

Practice Implications: Future interventions should target a more homogeneous sample and address counselees' understanding and recall.
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http://dx.doi.org/10.1016/j.pec.2018.05.009DOI Listing
September 2018

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Hum Mutat 2018 05 12;39(5):593-620. Epub 2018 Mar 12.

Lunenfeld-Tanenbaum Research Institute, Toronto, Canada.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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http://dx.doi.org/10.1002/humu.23406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903938PMC
May 2018

Role of germline aberrations affecting , and in gastric cancer susceptibility.

J Med Genet 2018 10 12;55(10):669-674. Epub 2018 Jan 12.

Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.

Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes , or .

Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a germline mutation for germline variants affecting , and using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.

Results: Predicted deleterious germline variants were not encountered in , but recurrently observed in (n=2) and (n=3) in our cohort of patients with GC. In contrast to deleterious variants in , deleterious variants in also occur frequently in the general population.

Conclusions: Based on our results should no longer be considered a GC predisposition gene, whereas deleterious variants are confirmed as an infrequent cause of GC susceptibility. Biallelic germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
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http://dx.doi.org/10.1136/jmedgenet-2017-104962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161648PMC
October 2018

An E-Learning Module to Improve Nongenetic Health Professionals' Assessment of Colorectal Cancer Genetic Risk: Feasibility Study.

JMIR Med Educ 2017 Dec 18;3(2):e24. Epub 2017 Dec 18.

Department of Medical Psychology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Background: Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling.

Objective: The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists.

Methods: A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires.

Results: A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest.

Conclusions: This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills.
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http://dx.doi.org/10.2196/mededu.7173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748476PMC
December 2017

Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations.

Dis Colon Rectum 2018 Jan;61(1):58-66

Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Background: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation.

Objective: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation.

Design: This was an historical cohort study.

Settings: This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom.

Patients: We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy.

Main Outcome Measures: The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas.

Results: Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas.

Limitations: This study was limited by its retrospective design, selection bias, and small sample size.

Conclusions: Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.
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http://dx.doi.org/10.1097/DCR.0000000000000868DOI Listing
January 2018

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet 2017 Dec 23;49(12):1767-1778. Epub 2017 Oct 23.

Department of Epidemiology, University of California, Irvine, Irvine, California, USA.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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http://dx.doi.org/10.1038/ng.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808456PMC
December 2017

Adrenal Lesions in Patients With (Attenuated) Familial Adenomatous Polyposis and MUTYH-Associated Polyposis.

Dis Colon Rectum 2017 Oct;60(10):1057-1064

1 Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 2 Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 3 Department of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 4 Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 5 Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 6 Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Background: The reported proportion of patients with familial adenomatous polyposis who have adrenal lesions varies between 7% and 13% compared with 4% in the general population; the prevalence of adrenal lesions in patients with attenuated familial adenomatous polyposis and MUTYH-associated polyposis is unknown. Data on the clinical relevance and clinical course are limited.

Objective: We aimed to report on the frequency, characteristics, and progression of adrenal lesions in polyposis patients.

Design: This was a historical cohort study.

Settings: The study was performed at the Academic Medical Center, Amsterdam.

Patients: All of the patients with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis were included. Medical charts and imaging reports were analyzed for data on adrenal lesions. A radiologist reassessed all of the images. Patients had not routinely been screened for adrenal lesions.

Main Outcome Measures: The frequency, characteristics, and progression of adrenal lesions in patients with polyposis who underwent abdominal imaging were assessed. Findings were compared with a reference.

Results: A total of 39 adrenal lesions were identified in 23 (26%) of 90 patients with familial adenomatous polyposis, 2 (18%) of 11 with attenuated familial adenomatous polyposis, and 5 (24%) of 21 with MUTYH-associated polyposis. Mean age at time of detection was 50.7 years (range, 17.1-83.3 y). Median lesion size at baseline was 1.4 cm (range, 1.0-5.0 cm) versus 1.7 cm (range, 1.0-5.7 cm) after a median of 3.5 years (range, 1.0-11.4 y). Two patients were diagnosed with a hyperfunctioning lesion, and 4 underwent adrenalectomy: 3 lesions appeared benign, and 1 was oncocytic of uncertain malignant potential. The OR for detecting at least 1 lesion in a patient with polyposis versus reference was 6.2 (95% CI, 3.2-12.3), with no significant differences in ORs among the 3 syndromes.

Limitations: The study was limited by its retrospective design.

Conclusions: Adrenal lesions are frequent in patients with polyposis who undergo abdominal imaging. They appear to follow a benign and slowly progressive course and are mostly nonhyperfunctioning. See Abstract Video at http://links.lww.com/DCR/A323.
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http://dx.doi.org/10.1097/DCR.0000000000000809DOI Listing
October 2017

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

Eur J Hum Genet 2017 11 6;25(11):1246-1252. Epub 2017 Sep 6.

Institute of Genomic Medicine, Catholic University of the Sacred Heart, Rome, Italy.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
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http://dx.doi.org/10.1038/ejhg.2017.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643972PMC
November 2017

Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation.

Eur J Cancer 2017 07 23;80:48-54. Epub 2017 May 23.

Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address:

Introduction: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation.

Methods: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist.

Results: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS.

Conclusion: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour.
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http://dx.doi.org/10.1016/j.ejca.2017.04.021DOI Listing
July 2017

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet 2017 May 27;49(5):680-691. Epub 2017 Mar 27.

N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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http://dx.doi.org/10.1038/ng.3826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612337PMC
May 2017

Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

Cancer Res 2017 06 10;77(11):2789-2799. Epub 2017 Mar 10.

Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.

Breast cancer risks conferred by many germline missense variants in the and genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508554PMC
June 2017

Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): protocol for a prospective, observational, multicentre study.

BMJ Open 2017 01 20;7(1):e013237. Epub 2017 Jan 20.

Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.

Introduction: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer.

Methods And Analysis: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument.

Ethics And Dissemination: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres.

Trial Registration Number: NTR5605.
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http://dx.doi.org/10.1136/bmjopen-2016-013237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253556PMC
January 2017

Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer.

Pancreas 2017 01;46(1):28-34

From the *Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam; †Department of Clinical Genetics, Academic Medical Center; and ‡Family Cancer Clinic Cancer Institute, Amsterdam; Departments of §Radiology and ∥Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam; ¶Department of Radiology, Academic Medical Center, Amsterdam; #Department of Genetics, University of Groningen, and **Department of Gastroenterology and Hepatology, University Medical Center, Groningen; Departments of ††Gastroenterology and Hepatology and ‡‡Clinical Genetics, University Medical Center, Utrecht; and §§Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.

Objectives: The aim of this study was to compare the prevalence of cystic pancreatic lesions and their natural behavior in 2 distinct high-risk groups for developing pancreatic ductal adenocarcinoma (PDAC): (1) carriers of a mutation that predisposes to PDAC and (2) individuals without a known gene mutation but with a family history of PDAC (familial pancreatic cancer [FPC]).

Methods: Pancreatic surveillance by annual magnetic resonance imaging and endoscopic ultrasound was performed in individuals with an estimated lifetime risk of developing PDAC of 10% or greater. Progression of a lesion was defined as growth 4 mm or greater or the development of worrisome features.

Results: We included 186 individuals: 98 mutation carriers and 88 FPC individuals (mean follow-up, 51 months). Individuals with FPC were significantly more likely than mutation carriers to have a pancreatic cyst 10 mm or greater (16% vs 5%, P = 0.045). Pancreatic cysts detected in mutation carriers, however, were significantly more likely to progress than those in FPC individuals (16% vs 2%, P = 0.050).

Conclusions: This study provides evidence that the prevalence and growth characteristics of pancreatic cysts differ between distinct high-risk groups: individuals with FPC have a higher prevalence of pancreatic cysts 10 mm or greater, whereas cysts in mutation carriers are more likely to progress. These observations may help to develop more optimally tailored surveillance strategies in specific high-risk populations.
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http://dx.doi.org/10.1097/MPA.0000000000000725DOI Listing
January 2017
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