Background and Aims: Previous trials comparing cyclo-sporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclo-sporine (C0), leading... Show moreBackground and Aims: Previous trials comparing cyclo-sporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclo-sporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tac-rolimus based on trough level (T0) after LT, with similar treat-ed biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. There-fore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT. Methods: Patients after first LT were randomized to C2 or T0. tBPAR, patient-and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test. Results: In intention-to- treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p <= 0.001), with no other differences in safety and tolerability. Conclusions: In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2. Show less
Potjer, T.P.; Grinten, T.W.J. van der; Lakeman, I.M.M.; Bollen, S.H.; Rodriguez-Girondo, M.; Iles, M.M.; ... ; Stoep, N. van der 2022
BACKGROUND & AIMS: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western... Show moreBACKGROUND & AIMS: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases.METHODS: Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies.RESULTS: Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I-2 = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I-2 = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd.CONCLUSIONS: Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives. Show less
Petzke, T.M.; Rodriguez-Girondo, M.; Meer, L.B. van der 2022
Background: A positive predictive genetic test for Huntington's disease (HD) can be a life-changing event for both carriers and their partners, leading to lower wellbeing and increasing the risk... Show moreBackground: A positive predictive genetic test for Huntington's disease (HD) can be a life-changing event for both carriers and their partners, leading to lower wellbeing and increasing the risk for separation and divorce. The 'Hold me Tight' program (HmT), based on emotionally focused couples' therapy, aims at strengthening the couple bond by targeting attachment needs.Objective: This study investigates whether the HmT program helps couples strengthen their relationship, as an investment in a future where the disease will affect life in many ways.Methods: In a multiple baseline design using three baselines of varying length, 15 couples of presymptomatic HD-carriers and their partners were included. In three consecutive groups, couples underwent the intervention (an adapted version of the 8-session HmT program) in four weekly sessions and completed self-report questionnaires throughout the study period of 19 weeks (17 measurements). Attachment style was assessed at baseline, resilience at baseline and at the end of the follow-up, while relationship satisfaction and wellbeing were measured weekly. A multi-level model was applied to the data.Results: Over the course of the study, wellbeing and relationship satisfaction significantly improved; resilience, however, did not. Furthermore, all three outcome measures were moderated by attachment style, with more securely attached individuals showing better outcomes.Conclusion: HmT improved wellbeing and relationship satisfaction of couples facing HD. Due to these improvements and high patient acceptability rates, this program could become a standardized procedure in HD care. The program could be adapted for other populations, e.g., couples facing other genetic neurological disorders. Show less
Potjer, T.P.; Grinten, T.W.J. van der; Lakeman, I.M.M.; Bollen, S.H.; Rodriguez-Girondo, M.; Iles, M.M.; ... ; Stoep, N. van der 2021
Background Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma... Show moreBackground Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. Methods Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. Results The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). Conclusion Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families. Show less
Rodriguez-Girondo, M.; Berg, N. van den; Hof, M.H.; Beekman, M.; Slagboom, E. 2021
Background: Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited... Show moreBackground: Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited success is the selection of participants. Studies generally include sporadically long-lived individuals, i.e. individuals with the longevity phenotype but without a genetic predisposition for longevity. The inclusion of these individuals causes phenotype heterogeneity which results in power reduction and bias. A way to avoid sporadically long-lived individuals and reduce sample heterogeneity is to include family history of longevity as selection criterion using a longevity family score. A main challenge when developing family scores are the large differences in family size, because of real differences in sibship sizes or because of missing data.Methods: We discussed the statistical properties of two existing longevity family scores: the Family Longevity Selection Score (FLoSS) and the Longevity Relatives Count (LRC) score and we evaluated their performance dealing with differential family size. We proposed a new longevity family score, the mLRC score, an extension of the LRC based on random effects modeling, which is robust for family size and missing values. The performance of the new mLRC as selection tool was evaluated in an intensive simulation study and illustrated in a large real dataset, the Historical Sample of the Netherlands (HSN).Results: Empirical scores such as the FLOSS and LRC cannot properly deal with differential family size and missing data. Our simulation study showed that mLRC is not affected by family size and provides more accurate selections of long-lived families. The analysis of 1105 sibships of the Historical Sample of the Netherlands showed that the selection of long-lived individuals based on the mLRC score predicts excess survival in the validation set better than the selection based on the LRC score .Conclusions: Model-based score systems such as the mLRC score help to reduce heterogeneity in the selection of long-lived families. The power of future studies into the genetics of longevity can likely be improved and their bias reduced, by selecting long-lived cases using the mLRC. Show less
Chiara, L. de; Leiro-Fernandez, V.; Rodriguez-Girondo, M.; Valverde, D.; Botana-Rial, M.I.; Fernandez-Villar, A. 2020
Different methodological approaches are available to assess DNA methylation biomarkers. In this study, we evaluated two sodium bisulfite conversion-dependent methods, namely pyrosequencing and... Show moreDifferent methodological approaches are available to assess DNA methylation biomarkers. In this study, we evaluated two sodium bisulfite conversion-dependent methods, namely pyrosequencing and methylation-specific qPCR (MS-qPCR), with the aim of measuring the closeness of agreement of methylation values between these two methods and its effect when setting a cut-off. Methylation of tumor suppressor gene p16/INK4A was evaluated in 80 lung cancer patients from which cytological lymph node samples were obtained. Cluster analyses were used to establish methylated and unmethylated groups for each method. Agreement and concordance between pyrosequencing and MS-qPCR was evaluated with Pearson's correlation, Bland-Altman, Cohen's kappa index and ROC curve analyses. Based on these analyses, cut-offs were derived for MS-qPCR. An acceptable correlation (Pearson's R2 = 0.738) was found between pyrosequencing (PYRmean) and MS-qPCR (NMP; normalized methylation percentage), providing similar clinical results when categorizing data as binary using cluster analysis. Compared to pyrosequencing, MS-qPCR tended to underestimate methylation for values between 0 and 15%, while for methylation >30% overestimation was observed. The estimated cut-off for MS-qPCR data based on cluster analysis, kappa-index agreement and ROC curve analysis were much lower than that derived from pyrosequencing. In conclusion, our results indicate that independently of the approach used for estimating the cut-off, the methylation percentage obtained through MS-qPCR is lower than that calculated for pyrosequencing. These differences in data and therefore in the cut-off should be examined when using methylation biomarkers in the clinical practice. Show less
Mourits, R.J.; Berg, N. van den; Rodriguez-Girondo, M.; Mandemakers, K.; Slagboom, P.E.; Beekman, M.; Janssens, A.A.P.O. 2020
Studies have shown that long-lived individuals seem to pass their survival advantage on to their offspring. Offspring of long-lived parents had a lifelong survival advantage over individuals... Show moreStudies have shown that long-lived individuals seem to pass their survival advantage on to their offspring. Offspring of long-lived parents had a lifelong survival advantage over individuals without long-lived parents, making them more likely to become long-lived themselves. We test whether the survival advantage enjoyed by offspring of long-lived individuals is explained by environmental factors. 101,577 individuals from 16,905 families in the 1812-1886 Zeeland cohort were followed over time. To prevent that certain families were overrepresented in our data, disjoint family trees were selected. Offspring was included if the age at death of both parents was known. Our analyses show that multiple familial resources are associated with survival within the first 5 years of life, with stronger maternal than paternal effects. However, between ages 5 and 100 both parents contribute equally to offspring's survival chances. After age 5, offspring of long-lived fathers and long-lived mothers had a 16-19% lower chance of dying at any given point in time than individuals without long-lived parents. This survival advantage is most likely genetic in nature, as it could not be explained by other, tested familial resources and is transmitted equally by fathers and mothers. Show less
Lakeman, I.M.M.; Rodriguez-Girondo, M.; Lee, A.; Ruiter, R.; Stricker, B.H.; Wijnant, S.R.A.; ... ; Devilee, P. 2020
Purpose We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort,... Show morePurpose We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. Methods Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS(313)was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS(313)and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results In total, 320 women developed BC. The PRS(313)was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions The effect size of the PRS(313)is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population. Show less
Berg, N. van den; Rodriguez-Girondo, M.; Mandemakers, K.; Janssens, A.A.P.O.; Beekman, M.; Slagboom, P.E. 2020
Loci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However,... Show moreLoci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However, identifying such loci is challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with the heritable longevity trait among long-living phenocopies. To avoid phenocopies, family selection scores have been constructed, but these have not yet been adopted as state of the art in longevity research. Here, we aim to identify individuals with the heritable longevity trait by using current insights and a novel family score based on these insights. We use a unique dataset connecting living study participants to their deceased ancestors covering 37,825 persons from 1,326 five-generational families, living between 1788 and 2019. Our main finding suggests that longevity is transmitted for at least two subsequent generations only when at least 20% of all relatives are long-lived. This proves the importance of family data to avoid phenocopies in genetic studies. Show less
Heijs, B.; Holst-Bernal, S.; Graaff, M.A. de; Briaire-de Bruijn, I.H.; Rodriguez-Girondo, M.; Sande, M.A.J. van de; ... ; Bovee, J.V.M.G. 2020
Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, accounting for 6% of all sarcomas. MLS is characterized by a pathognomonic FUS-DDIT3, or rarely EWSR1-DDIT3, gene fusion.... Show moreMyxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, accounting for 6% of all sarcomas. MLS is characterized by a pathognomonic FUS-DDIT3, or rarely EWSR1-DDIT3, gene fusion. The presence of >= 5% hypercellular round cell areas is associated with a worse prognosis for the patient and is considered high grade. The prognostic significance of areas with moderately increased cellularity (intermediate) is currently unknown. Here we have applied matrix-assisted laser desorption/ionization mass spectrometry imaging to analyze the spatial distribution of N-linked glycans on an MLS microarray in order to identify molecular markers for tumor progression. Comparison of the N-glycan profiles revealed that increased relative abundances of high-mannose type glycans were associated with tumor progression. Concomitantly, an increase of the average number of mannoses on high-mannose glycans was observed. Although overall levels of complex-type glycans decreased, an increase of tri- and tetra-antennary N-glycans was observed with morphological tumor progression and increased tumor histological grade. The high abundance of tri-antennary N-glycan species was also associated with poor disease-specific survival. These findings mirror recent observations in colorectal cancer, breast cancer, ovarian cancer, and cholangiocarcinoma, and are in line with a general role of high-mannose glycans and higher-antennary complex-type glycans in cancer progression. Show less
Roos, V.H.; Mangas-Sanjuan, C.; Rodriguez-Girondo, M.; Medina-Prado, L.; Steyerberg, E.W.; Bossuyt, P.M.M.; ... ; Leerdam, M.E. van 2019
Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of... Show moreCarriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients' surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR - 0.703 [95% CI - 1.201 to - 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined. Show less
Lakeman, I.M.M.; Hilbers, F.S.; Rodriguez-Girondo, M.; Lee, A.; Vreeswijk, M.P.G.; Hollestelle, A.; ... ; Devilee, P. 2019
Background The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that... Show moreBackground The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families.Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS.Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively.Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families. Show less
Christodoulou, E.; Visser, M.; Potjer, T.P.; Stoep, N. van der; Rodriguez-Girondo, M.; Doorn, R. van; Gruis, N. 2019
Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of... Show moreCarriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients’ surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR -0.703 [95% CI -1.201-0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined. Show less
Lakeman, I.M.M.; Hilbers, F.S.; Rodriguez-Girondo, M.; Lee, A.; Vreeswijk, M.P.G.; Hollestelle, A.; ... ; Devilee, P. 2019
Background The currently known breast cancer associated Single Nucleotide Polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that... Show moreBackground The currently known breast cancer associated Single Nucleotide Polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based Polygenic Risk Score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the BOADICEA breast cancer lifetime risk with the effect of the sPRS. Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95%CI=1.03-1.28, P=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7%, and 19.8% of the women according to breast screening guidelines from the United States of America (NCCN), United Kingdom (NICE), and the Netherlands (IKNL), respectively. Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families. Show less
Berg, N. van den; Rodriguez-Girondo, M.; Dijk, I.K. van; Mourits, R.J.; Mandemakers, K.; Janssens, A.A.P.O.; ... ; Slagboom, P.E. 2019
To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance... Show moreTo establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA, BRCAPRO and the Myriad prevalence table ('Myriad'). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed versus predicted carriers and assessed the area under the receiver operating characteristic (ROC) curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% Confidence Interval (CI): (0.60-1.09) and 0.79, 95% CI: (0.57-1.09), vs. BRCAPRO: 1.02, 95% CI: (0.75-1.38) and 0.94, 95% CI: (0.68-1.31), respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources. Show less
Blanco-Prieto, S.; Chiara, L. de; Rodriguez-Girondo, M.; Vazquez-Iglesias, L.; Rodriguez-Berrocal, F.J.; Fernandez-Villar, A.; ... ; Cadena, M.P. de la 2017
