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Article ; Online: Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

van de Beek, Irma / Glykofridis, Iris E / Wagner, Anja / den Toom, Dorine T / Bongers, Ernie M H F / van Leenders, Geert J L H / Johannesma, Paul C / Meijers-Heijboer, Hanne E J / Wolthuis, Rob M F / van Steensel, Maurice A M / Dubbink, Hendrikus J / Houweling, Arjan C

Molecular genetics & genomic medicine

2022 Volume 11, Issue 2, Page(s) e2098

Abstract: Background: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three ... ...

Abstract	Background: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17. Methods: We describe the phenotype and performed single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) analysis of the tumors. Results: All examined tumors showed somatic loss of the wild-type alleles of both FLCN and TP53. Conclusions: We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.
MeSH term(s)	Humans ; Carcinoma, Renal Cell/genetics ; Kidney Neoplasms/genetics ; Tumor Suppressor Proteins/genetics ; Genetic Predisposition to Disease ; Brain Neoplasms ; Germ Cells/metabolism ; Germ Cells/pathology ; Tumor Suppressor Protein p53/genetics ; Proto-Oncogene Proteins/genetics
Chemical Substances	Tumor Suppressor Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; FLCN protein, human ; Proto-Oncogene Proteins
Language	English
Publishing date	2022-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.2098
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Article ; Online: PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

van de Beek, Irma / Glykofridis, Iris E / Oosterwijk, Jan C / van den Akker, Peter C / Diercks, Gilles F H / Bolling, Maria C / Waisfisz, Quinten / Mensenkamp, Arjen R / Balk, Jesper A / Zwart, Rob / Postma, Alex V / Meijers-Heijboer, Hanne E J / van Moorselaar, R Jeroen A / Wolthuis, Rob M F / Houweling, Arjan C

Human molecular genetics

2022 Volume 32, Issue 7, Page(s) 1223–1235

Abstract: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, ... ...

Abstract	Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas.
MeSH term(s)	Humans ; Birt-Hogg-Dube Syndrome/genetics ; Birt-Hogg-Dube Syndrome/pathology ; Carcinoma, Renal Cell/genetics ; Genes, Tumor Suppressor ; Skin Neoplasms/genetics ; Lipomatosis/genetics ; Kidney Neoplasms/genetics ; DNA-Binding Proteins/genetics ; Transcription Factors/genetics ; Proto-Oncogene Proteins/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	PRDM10 protein, human ; DNA-Binding Proteins ; Transcription Factors ; FLCN protein, human ; Proto-Oncogene Proteins ; Tumor Suppressor Proteins
Language	English
Publishing date	2022-11-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddac288
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Zs.A 3469: Show issues

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Article: Clonality, Antigen Recognition, and Suppression of CD8

Hammerl, Dora / Massink, Maarten P G / Smid, Marcel / van Deurzen, Carolien H M / Meijers-Heijboer, Hanne E J / Waisfisz, Quinten / Debets, Reno / Martens, John W M

Clinical cancer research : an official journal of the American Association for Cancer Research

2019 Volume 26, Issue 2, Page(s) 505–517

Abstract: Purpose: In breast cancer, response rates to immune therapies are generally low and differ significantly across molecular subtypes, urging a better understanding of immunogenicity and immune evasion.: Experimental design: We interrogated large gene- ... ...

Abstract	Purpose: In breast cancer, response rates to immune therapies are generally low and differ significantly across molecular subtypes, urging a better understanding of immunogenicity and immune evasion. Experimental design: We interrogated large gene-expression data sets including 867 node-negative, treatment-naïve breast cancer patients (microarray data) and 347 breast cancer patients (whole-genome sequencing and transcriptome data) according to parameters of T cells as well as immune microenvironment in relation to patient survival. Results: We developed a 109-immune gene signature that captures abundance of CD8 tumor-infiltrating lymphocytes (TIL) and is prognostic in basal-like, her2, and luminal B breast cancer, but not in luminal A or normal-like breast cancer. Basal-like and her2 are characterized by highest CD8 TIL abundance, highest T-cell clonality, highest frequencies of memory T cells, and highest antigenicity, yet only the former shows highest expression level of immune and metabolic checkpoints and highest frequency of myeloid suppressor cells. Also, luminal B shows a high antigenicity and T-cell clonality, yet a low abundance of CD8 TILs. In contrast, luminal A and normal-like both show a low antigenicity, and notably, a low and high abundance of CD8 TILs, respectively, which associates with T-cell influx parameters, such as expression of adhesion molecules. Conclusions: Collectively, our data argue that not only CD8 T-cell presence itself, but rather T-cell clonality, T-cell subset distribution, coinhibition, and antigen presentation reflect occurrence of a CD8 T-cell response in breast cancer subtypes, which have been aborted by distinct T-cell-suppressive mechanisms, providing a rationale for subtype-specific combination immune therapies.
MeSH term(s)	Antigen Presentation/immunology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/immunology ; Breast Neoplasms/classification ; Breast Neoplasms/genetics ; Breast Neoplasms/immunology ; Breast Neoplasms/mortality ; CD8-Positive T-Lymphocytes/immunology ; Clone Cells/immunology ; Databases, Genetic/statistics & numerical data ; Female ; Gene Expression Profiling ; Humans ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Prognosis ; Receptor, ErbB-2/metabolism ; Survival Rate ; T-Lymphocyte Subsets/immunology ; Tumor Microenvironment/immunology
Chemical Substances	Biomarkers, Tumor ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2019-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-19-0285
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Zs.A 4223: Show issues

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Article ; Online: Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics.

Kleinendorst, Lotte / Abawi, Ozair / van der Kamp, Hetty J / Alders, Mariëlle / Meijers-Heijboer, Hanne E J / van Rossum, Elisabeth F C / van den Akker, Erica L T / van Haelst, Mieke M

European journal of endocrinology

2019 Volume 182, Issue 1, Page(s) 47–56

Abstract: Objective: Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing ... ...

Abstract	Objective: Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe. Design: Comprehensive epidemiologic analysis and systematic literature review. Methods: We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants. Results: Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95-1.72). Conclusions: This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.
MeSH term(s)	Female ; Genetics, Population/methods ; Humans ; Male ; Prevalence ; Receptors, Leptin/deficiency ; Receptors, Leptin/genetics
Chemical Substances	LEPR protein, human ; Receptors, Leptin
Language	English
Publishing date	2019-11-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1530/EJE-19-0678
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Article ; Online: No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome.

van de Beek, Irma / Glykofridis, Iris E / Wolthuis, Rob M F / Gille, Hans J J P / Johannesma, Paul C / Meijers-Heijboer, Hanne E J / Moorselaar, R Jeroen A van / Houweling, Arjan C

British journal of cancer

2019 Volume 122, Issue 4, Page(s) 590–594

Abstract: Background: Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch patients with Birt-Hogg-Dubé syndrome and ... ...

Abstract	Background: Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch patients with Birt-Hogg-Dubé syndrome and their relatives without Birt-Hogg-Dubé syndrome. Methods: In all, 399 patients with a pathogenic FLCN mutation and 382 relatives without the familial FLCN mutation were included. Anonymous data on colon and rectum pathology was provided by PALGA: the Dutch Pathology Registry. Results: No significant difference in the percentage of individuals with a history of colorectal carcinoma was found between the two groups (3.6% vs 2.6%, p = 0.54). There was also no significant difference between the age at diagnosis, diameter, differentiation and location of the colorectal carcinomas. Significantly more individuals with Birt-Hogg-Dubé syndrome underwent removal of colorectal polyps (12.2% vs 6.3%, p = 0.005). However, there was no significant difference between the number of polyps per person, the histology, grade of dysplasia and location of the polyps. Conclusion: Our data do not provide evidence for an increased risk for colorectal carcinoma in Birt-Hogg-Dubé syndrome, arguing against the need for colorectal surveillance. The difference in polyps might be due to a bias caused by a higher number of colonoscopies in patients with Birt-Hogg-Dubé syndrome.
MeSH term(s)	Aged ; Birt-Hogg-Dube Syndrome/complications ; Colorectal Neoplasms/epidemiology ; Female ; Humans ; Male ; Middle Aged ; Netherlands/epidemiology ; Prevalence
Language	English
Publishing date	2019-12-20
Publishing country	England
Document type	Journal Article
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-019-0693-1
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Article ; Online: Increased prevalence of BRCA1/2 mutations in women with macrotextured breast implants and anaplastic large cell lymphoma of the breast.

de Boer, Mintsje / Hauptmann, Michael / Hijmering, Nathalie J / van Noesel, Carel J M / Rakhorst, Hinne A / Meijers-Heijboer, Hanne E J / de Boer, Jan Paul / van der Hulst, René R W J / de Jong, Daphne / van Leeuwen, Flora E

Blood

2020 Volume 136, Issue 11, Page(s) 1368–1372

MeSH term(s)	Adult ; Age Distribution ; Aged ; Breast Implants/adverse effects ; Breast Implants/statistics & numerical data ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease ; Humans ; Lymphoma, Large-Cell, Anaplastic/epidemiology ; Lymphoma, Large-Cell, Anaplastic/genetics ; Lymphoma, Large-Cell, Anaplastic/therapy ; Mammaplasty ; Middle Aged ; Mutation ; Netherlands/epidemiology ; Prophylactic Mastectomy ; Risk ; Surface Properties ; Time Factors
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Letter
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019004498
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Article ; Online: Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates.

Henneman, Peter / Bouman, Arjan / Mul, Adri / Knegt, Lia / van der Kevie-Kersemaekers, Anne-Marie / Zwaveling-Soonawala, Nitash / Meijers-Heijboer, Hanne E J / van Trotsenburg, A S Paul / Mannens, Marcel M

PloS one

2018 Volume 13, Issue 3, Page(s) e0194938

Abstract: Introduction: Down syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained ... ...

Abstract	Introduction: Down syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. This study aimed to investigate genome-wide methylation patterns in DS newborns compared to non-trisomic newborns. Method: We analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution. Results: Differentially methylated position (DMP) analysis of the uncorrected model detected 19525 significant hits (51,2% hypomethylated). In the corrected model, we found 121953 significant DMPs (49,8% hypomethylated). Independent of the used model we observed a chromosome 21 dosage effect. Moreover, we detected 46 and 145 differentially methylated regions in the uncorrected and corrected model respectively, both showing hypomethylation overrepresentation. Replication analyses of DMPs and DMRs found by Bacalini et al. (2015) showed a large overlap. Conclusion: In this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21. Additional research is necessary to substantiate these hypotheses.
MeSH term(s)	DNA Methylation ; Down Syndrome/blood ; Down Syndrome/genetics ; Epigenesis, Genetic ; Female ; Genomics ; Humans ; Infant, Newborn ; Male
Language	English
Publishing date	2018-03-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0194938
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Article ; Online: Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome.

Johannesma, Paul C / van de Beek, Irma / van der Wel, Tijmen J W T / Reinhard, Rinze / Rozendaal, Lawrence / Starink, Theo M / van Waesberghe, Jan Hein T M / Horenblas, Simon / Gille, Hans J J P / Jonker, Marianne A / Meijers-Heijboer, Hanne E J / Postmus, Pieter E / Houweling, Arjan C / van Moorselaar, Jeroen R A

PloS one

2019 Volume 14, Issue 3, Page(s) e0212952

Abstract: Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC ... ...

Abstract	Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7-27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Birt-Hogg-Dube Syndrome/complications ; Birt-Hogg-Dube Syndrome/genetics ; Carcinoma, Renal Cell/diagnostic imaging ; Carcinoma, Renal Cell/genetics ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Humans ; Kidney/diagnostic imaging ; Kidney Neoplasms/diagnostic imaging ; Kidney Neoplasms/genetics ; Magnetic Resonance Imaging ; Male ; Mass Screening/methods ; Mass Screening/statistics & numerical data ; Middle Aged ; Netherlands ; Patient Compliance/statistics & numerical data ; Proto-Oncogene Proteins/genetics ; Retrospective Studies ; Tomography, X-Ray Computed ; Tumor Suppressor Proteins/genetics ; Ultrasonography ; Young Adult
Chemical Substances	FLCN protein, human ; Proto-Oncogene Proteins ; Tumor Suppressor Proteins
Language	English
Publishing date	2019-03-07
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0212952
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Article ; Online: Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.

Heemskerk-Gerritsen, Bernadette A M / Jager, Agnes / Koppert, Linetta B / Obdeijn, A Inge-Marie / Collée, Margriet / Meijers-Heijboer, Hanne E J / Jenner, Denise J / Oldenburg, Hester S A / van Engelen, Klaartje / de Vries, Jakob / van Asperen, Christi J / Devilee, Peter / Blok, Marinus J / Kets, C Marleen / Ausems, Margreet G E M / Seynaeve, Caroline / Rookus, Matti A / Hooning, Maartje J

Breast cancer research and treatment

2019 Volume 177, Issue 3, Page(s) 723–733

Abstract: Background: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet.: Methods: ... ...

Abstract	Background: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. Methods: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/etiology ; Breast Neoplasms/mortality ; Breast Neoplasms/prevention & control ; Breast Neoplasms/surgery ; Female ; Germ-Line Mutation ; Heterozygote ; Humans ; Mortality ; Mutation ; Netherlands/epidemiology ; Prognosis ; Prophylactic Mastectomy/methods ; Public Health Surveillance ; Risk Reduction Behavior
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human
Language	English
Publishing date	2019-07-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-019-05345-2
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Zs.A 1655: Show issues

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Article ; Online: Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis.

Heemskerk-Gerritsen, Bernadette A M / Rookus, Matti A / Aalfs, Cora M / Ausems, Margreet G E M / Collée, Johanna M / Jansen, Liesbeth / Kets, C Marleen / Keymeulen, Kristien B M I / Koppert, Linetta B / Meijers-Heijboer, Hanne E J / Mooij, Thea M / Tollenaar, Rob A E M / Vasen, Hans F A / Hooning, Maartje J / Seynaeve, Caroline

International journal of cancer

2015 Volume 136, Issue 3, Page(s) 668–677

Abstract: Data on survival of BRCA1/2-associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk-reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a ...

Abstract	Data on survival of BRCA1/2-associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk-reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a history of PBC. From a Dutch multicentre cohort, we selected 583 BRCA-associated PBC patients, being diagnosed between 1980 and 2011. Over time, 242 patients (42%) underwent CRRM and 341 patients (58%) remained under surveillance. Survival analyses were performed using Cox models, with CRRM as a time-dependent covariate. The median follow-up after PBC diagnosis was 11.4 years. In the CRRM group, four patients developed contralateral breast cancer (2%), against 64 patients (19%) in the surveillance group (p < 0.001). The mortality was lower in the CRRM group than in the surveillance group (9.6 and 21.6 per 1000 person-years of observation, respectively; adjusted hazard ratio 0.49, 95% confidence interval 0.29-0.82). Survival benefit was especially seen in young PBC patients (<40 years), in patients having a PBC with differentiation grade 1/2 and/or no triple-negative phenotype, and in patients not treated with adjuvant chemotherapy. We conclude that CRRM is associated with improved overall survival in BRCA1/2 mutation carriers with a history of PBC. Further research is warranted to develop a model based on age at diagnosis and tumour and treatment characteristics that can predict survival benefit for specific subgroups of patients, aiming at further personalized counselling and improved decision making.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/surgery ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Mastectomy ; Middle Aged ; Mutation ; Prospective Studies
Language	English
Publishing date	2015-02-01
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.29032
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 576: Show issues

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