[Show abstract][Hide abstract] ABSTRACT: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.
Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.
No significant association with pancreatic cancer was found for any of the seven SNPs.
Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.
BMC Research Notes 06/2015; 8:264. DOI:10.1186/s13104-015-1235-4
[Show abstract][Hide abstract] ABSTRACT: Despite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method.
In this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation.
In this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects.
Repeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific biomarkers.
PLoS ONE 05/2015; 10(5):e0127895. DOI:10.1371/journal.pone.0127895 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Journal of Medical Genetics 05/2015; 52(6). DOI:10.1136/jmedgenet-2015-103094 · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT.
Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits.
Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes.
In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.Genet Med advance online publication 23 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.50.
Genetics in medicine: official journal of the American College of Medical Genetics 04/2015; DOI:10.1038/gim.2015.50 · 6.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES:Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is expected that rapid genetic counseling and testing (RGCT) will lead to increasing numbers of breast cancer (BC) patients knowing their BRCA1/2 carrier status before primary surgery. Considering the potential impact of knowing one's status on uptake and timing of risk-reducing contralateral mastectomy (RRCM), we aimed to evaluate trends over time in RRCM, and differences between carriers identified either before (predictively) or after (diagnostically) diagnosis. We collected data from female BRCA1/2 mutation carriers diagnosed with BC between 1995 and 2009 from four Dutch university hospitals. We compared the timing of genetic testing and RRCM in relation to diagnosis in 1995-2000 versus 2001-2009 for all patients, and predictively and diagnostically tested patients separately. Of 287 patients, 219 (76 %) had a diagnostic BRCA1/2 test. In this cohort, the median time from diagnosis to DNA testing decreased from 28 months for those diagnosed between 1995 and 2000 to 14 months for those diagnosed between 2001 and 2009 (p < 0.001). Similarly, over time women in this cohort underwent RRCM sooner after diagnosis (median of 77 vs. 27 months, p = 0.05). Predictively tested women who subsequently developed BC underwent an immediate RRCM significantly more often than women who had a diagnostic test (21/61, 34 %, vs. 13/170, 7.6 %, p < 0.001). Knowledge of carrying a BRCA1/2 mutation when diagnosed with BC influenced decisions concerning primary surgery. Additionally, in more recent years, women who had not undergone predictive testing were more likely to undergo diagnostic DNA testing and RRCM sooner after diagnosis. This suggests the need for RGCT to guide treatment decisions.
Familial Cancer 02/2015; DOI:10.1007/s10689-015-9788-x · 1.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
[Show abstract][Hide abstract] ABSTRACT: Background:We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) over 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. Methods:This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with hazard ratios (HRs) and odds ratios (ORs). HRs were adjusted for birth year and mutation spectrum. Results:All BRCA1 carriers and BRCA2 carriers under age 60 had a significantly lower breast cancer risk in the Northern Netherlands, HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands (HR = 3.99, 95% CI 1.11-14.35). Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60 and BRCA2 ≥60 years by -3%, +32% and +11% to 0.75, 0.50 and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR = 1.03, 95% CI 0.97-1.09). Conclusions:Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. Impact:The increased risk in BRCA2 carriers over 60 may warrant extension of intensive breast screening beyond age 60.
[Show abstract][Hide abstract] ABSTRACT: IntroductionApproximately 70% of counselees undergoing cancer genetic counseling and testing (CGCT) experience some degree of CGCT-related psychosocial problems. We evaluated the efficacy of an intervention designed to increase detection and management of problems four weeks after completion of CGCT.Methods
In this randomized, controlled trial, 118 participants completed a CGCT-related problem questionnaire prior to an -audiotaped- telephone session with their counselor one month after DNA-test disclosure. For those randomized to the intervention group (n = 63), a summary of the questionnaire results was provided to the counselor prior to the telephone session. Primary outcomes were discussion of the problems, counselors’ awareness of problems, and problem management. Secondary outcomes included self-reported distress, cancer worries, CGCT-related problems, and satisfaction.ResultsCounselors who received a summary of the questionnaire were more aware of counselees’ problems in only one psychosocial domain (practical issues). No significant differences in the number of problems discussed, in problem management, or on any of the secondary outcomes were observed. The prevalence of problems was generally low.Conclusions
The telephone session, combined with feedback on psychosocial problems, has minimal impact. The low prevalence of psychosocial problems one month post-CGCT recommends against its use as a routine extension of the CGCT procedure.
[Show abstract][Hide abstract] ABSTRACT: Purpose This study evaluated the efficacy of a cancer genetics-specific questionnaire in facilitating communication about, awareness of, and management of psychosocial problems, as well as in lowering distress levels. Methods Individuals referred to genetic counseling for cancer at two family cancer clinics in the Netherlands were randomly assigned to an intervention or a control group. All participants completed the psychosocial questionnaire before counseling. In the intervention group, the counselors received the results of this questionnaire before the counseling session. All sessions were audiotaped for content analysis. Primary outcomes were the frequency with which psychosocial problems were discussed, the genetic counselors' awareness of these problems, and their management. Secondary outcomes included cancer worries and psychological distress, duration and dynamics of the counseling, and satisfaction. Results The frequency with which psychosocial problems were discussed with 246 participating counselees was significantly higher in the intervention group (n = 127) than in the control group (n = 119; P = .004), as was the counselors' awareness of psychosocial problems regarding hereditary predisposition (P < .001), living with cancer (P = .01), and general emotions (P < .001). Counselors initiated more discussion of psychosocial problems in the intervention group (P < .001), without affecting the length of the counseling session. No significant differences were found on management (P = .19). The intervention group reported significantly lower levels of cancer worries (P = .005) and distress (P = .02) after counseling. Conclusion The routine assessment of psychosocial problems by questionnaire facilitates genetic counselors' recognition and discussion of their clients' psychosocial problems and reduces clients' distress levels. (C) 2014 by American Society of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: The purpose of the study was to assess the counselee participation in the follow-up visits, compared to the first visits, for breast cancer genetic counselling and to explore associations with counselees' achievement of their preferred role in decision making, information recall, knowledge, risk perception alignment and perceived personal control. First and follow-up visits for breast cancer genetic counselling of 96 counselees of a Dutch genetics center were videotaped (2008-2010). Counselees completed questionnaires before counselling (T1), after the follow-up visit (T2) and one year after the follow-up visit (T3). Consultations were rated with the Roter Interaction Analysis System (RIAS). Counselee participation was measured as the percentage of counselee utterances, the percentage of counselee questions and the interactivity (number of turns per minute). Follow-up visits had higher levels of counselee participation than first visits as assessed by the percentage of counselee talk, the interactivity and counselee questions. More counselee talk in the follow-up visit was related to higher achievement of the preferred role (T2) and higher perceived personal control (T3). Higher interactivity in the follow-up visit was related to lower achievement of the preferred role in decision making and lower information recall (T2). There were no significant associations with the percentage of questions asked and none of the participation measures was related to knowledge, risk perception alignment and perceived personal control (T2). In line with the interviewing admonishment 'talk less and listen more', the only assessment of counselee participation associated to better outcomes is the percentage of counselee talk. High interactivity might be associated with lower recall in breast cancer genetic counselees who are generally highly educated. However, this study was limited by a small sample size and a heterogeneous group of counselees. Research is needed on the interactions causing interactivity and its relationships with involvement in decision making and recall.
Social Science & Medicine 07/2014; 116C:178-186. DOI:10.1016/j.socscimed.2014.07.012 · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations.
Methods We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model.
Results The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (pheterogeneity = 0.0006) and stronger family histories of breast cancer (pheterogeneity<0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location.
Conclusions BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.
Journal of Medical Genetics 02/2014; 51(2):98-107. DOI:10.1136/jmedgenet-2013-101974 · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.
To report the first year's screening results for all men at enrolment in the study.
We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy.
PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.
We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.
The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.
In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
European Urology 01/2014; 66(3). DOI:10.1016/j.eururo.2014.01.003 · 12.48 Impact Factor