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1. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

Author: Rhiem, Kerstin, Zachariae, Silke, Waha, Anke, Grill, Sabine, Hester, Anna, Golatta, Michael; https://orcid.org/0000-0002-2605-0060, van Mackelenbergh, Marion, Fehm, Tanja, Schlaiß, Tanja, Ripperger, Tim; https://orcid.org/0000-0001-6470-8612, Ledig, Susanne, Meisel, Cornelia, Speiser, Dorothee; https://orcid.org/0000-0002-6447-629X, Veselinovic, Kristina, Schröder, Christopher, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Gallwas, Julia, Weber, Bernhard H F; https://orcid.org/0000-0002-8808-7723, Solbach, Christine; https://orcid.org/0000-0001-8284-3199, Aktas, Bariyhe, Hahnen, Eric, Engel, Christoph; https://orcid.org/0000-0002-7247-282X, Schmutzler, Rita, Rhiem, Kerstin, Zachariae, Silke, Waha, Anke, Grill, Sabine, Hester, Anna, Golatta, Michael; https://orcid.org/0000-0002-2605-0060, van Mackelenbergh, Marion, Fehm, Tanja, Schlaiß, Tanja, Ripperger, Tim; https://orcid.org/0000-0001-6470-8612, Ledig, Susanne, Meisel, Cornelia, Speiser, Dorothee; https://orcid.org/0000-0002-6447-629X, Veselinovic, Kristina, Schröder, Christopher, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Gallwas, Julia, Weber, Bernhard H F; https://orcid.org/0000-0002-8808-7723, Solbach, Christine; https://orcid.org/0000-0001-8284-3199, Aktas, Bariyhe, Hahnen, Eric, Engel, Christoph; https://orcid.org/0000-0002-7247-282X, and Schmutzler, Rita
Abstract: Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19–78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression. Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21–1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years. Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.
Published: 2023

2. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

Author: Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Buttner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus Knebel, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, Engel, Christoph, Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Buttner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus Knebel, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, and Engel, Christoph
Abstract: Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
Published: 2022

3. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

Author: Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Hüneburg, Robert, Kloor, Matthias, von Knebel Doeberitz, Magnus, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Nguyen, Huu Phuc, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Jürgen, Loeffler, Markus, Engel, Christoph, for Familial Intestinal Cancer, German Consortium, Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Hüneburg, Robert, Kloor, Matthias, von Knebel Doeberitz, Magnus, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Nguyen, Huu Phuc, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Jürgen, Loeffler, Markus, Engel, Christoph, and for Familial Intestinal Cancer, German Consortium
Abstract: Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX. What's new? While associations between colorectal cancer (CRC) risk and Lynch syndrome (LS) are well-described, less is known about CRC risks linked to the closely related Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX). In this prospective follow-up study of patients with LS, LLS, and FCCX, risks were similar for colorectal adenomas but considerably different for first and metachronous CRCs. In addition, LS females who carried MSH2 mutations had notably higher CRC risks than female MLH1 mutation carriers. The identification of variations in carcinogenic pathways betwe
Published: 2022

4. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

Author: Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Hüneburg, Robert, Kloor, Matthias, von Knebel Doeberitz, Magnus, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Nguyen, Huu Phuc, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Jürgen, Loeffler, Markus, Engel, Christoph, for Familial Intestinal Cancer, German Consortium, Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Hüneburg, Robert, Kloor, Matthias, von Knebel Doeberitz, Magnus, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Nguyen, Huu Phuc, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Jürgen, Loeffler, Markus, Engel, Christoph, and for Familial Intestinal Cancer, German Consortium
Abstract: Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX. What's new? While associations between colorectal cancer (CRC) risk and Lynch syndrome (LS) are well-described, less is known about CRC risks linked to the closely related Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX). In this prospective follow-up study of patients with LS, LLS, and FCCX, risks were similar for colorectal adenomas but considerably different for first and metachronous CRCs. In addition, LS females who carried MSH2 mutations had notably higher CRC risks than female MLH1 mutation carriers. The identification of variations in carcinogenic pathways betwe
Published: 2022

5. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

Author: Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Buttner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus Knebel, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, Engel, Christoph, Bucksch, Karolin, Zachariae, Silke, Ahadova, Aysel, Aretz, Stefan, Buttner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus Knebel, Ladigan-Badura, Swetlana, Moeslein, Gabriela, Morak, Monika, Nattermann, Jacob, Perne, Claudia, Redler, Silke, Schmetz, Ariane, Steinke-Lange, Verena, Surowy, Harald, Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, and Engel, Christoph
Abstract: Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
Published: 2022

6. HerediCaRe: Documentation and IT Solution of a Specialized Registry for Hereditary Breast and Ovarian Cancer

Author: Engel, Christoph, Wieland, Kerstin, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Schoenwiese, Ulrike, Yahiaoui-Doktor, Maryam, Keupp, Katharina, Waha, Anke, Hahnen, Eric, Remy, Robert, Ernst, Corinna, Loeffler, Markus, Schmutzler, Rita K., Engel, Christoph, Wieland, Kerstin, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Schoenwiese, Ulrike, Yahiaoui-Doktor, Maryam, Keupp, Katharina, Waha, Anke, Hahnen, Eric, Remy, Robert, Ernst, Corinna, Loeffler, Markus, and Schmutzler, Rita K.
Abstract: Zusammenfassung Das nationale Register HerediCaRe fur die Evaluation und Verbesserung der risiko-adjustierten Pravention bei erblichem Brust- und Eierstockkrebs ist eines von sechs vom BMBF geforderten modellhaften Registern in der Versorgungsforschung. In diesem Beitrag beschreiben und diskutieren wir die zur standardisierten Datenerfassung gewahlte Dokumentations- und IT-Losung auf der Basis der zuvor definierten speziellen funktionalen Anforderungen. Die Dokumentation gliedert sich in verschiedene patientenindividuell einzusetzende Module, die auf einem zuvor festgelegten Merkmalskatalog beruhen. Aufgrund spezieller funktionaler Anforderungen wurde eine eigene Datenerfassungsanwendung auf der Basis von ORACLE und ORACLE Forms entwickelt und implementiert. Die speziellen Anforderungen umfassten u.a. die Einbindung grafischer Stammbaumdarstellungen, den strukturierten Upload von Stammbaumdaten und molekulargenetischen Informationen, die automatisierte Altdatenubernahme aus dem Vorgangersystem, sowie die freie Programmierbarkeit von beliebig komplexen Datenbankabfragen zur zentralen Datenqualitatsprufung. In die Anwendung ist eine Datenbank zur patienten-unabhangigen Verwaltung genetischer Risikovarianten nahtlos integriert und mit den patientenbezogenen Daten verknupft. Die Vor- und Nachteile der gewahlten IT-Losung werden kritisch diskutiert. Insgesamt kommen wir zu der Schlussfolgerung, dass es angesichts der komplexen Dokumentation und der speziellen Funktionsanforderungen alternativ keine fertigen Softwareprodukte zu der von uns gewahlten Eigenentwicklung existieren. Abstract The national registry HerediCaRe for the evaluation and improvement of risk-adjusted prevention in hereditary breast and ovarian cancer is one of six model registries in health services research funded by the BMBF. In this paper, we describe and discuss the documentation and IT solution chosen for standardized data collection based on the specific functional requirements previously defined
Published: 2021

7. HerediCaRe: Documentation and IT Solution of a Specialized Registry for Hereditary Breast and Ovarian Cancer

Author: Engel, Christoph, Wieland, Kerstin, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Schoenwiese, Ulrike, Yahiaoui-Doktor, Maryam, Keupp, Katharina, Waha, Anke, Hahnen, Eric, Remy, Robert, Ernst, Corinna, Loeffler, Markus, Schmutzler, Rita K., Engel, Christoph, Wieland, Kerstin, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Schoenwiese, Ulrike, Yahiaoui-Doktor, Maryam, Keupp, Katharina, Waha, Anke, Hahnen, Eric, Remy, Robert, Ernst, Corinna, Loeffler, Markus, and Schmutzler, Rita K.
Abstract: Zusammenfassung Das nationale Register HerediCaRe fur die Evaluation und Verbesserung der risiko-adjustierten Pravention bei erblichem Brust- und Eierstockkrebs ist eines von sechs vom BMBF geforderten modellhaften Registern in der Versorgungsforschung. In diesem Beitrag beschreiben und diskutieren wir die zur standardisierten Datenerfassung gewahlte Dokumentations- und IT-Losung auf der Basis der zuvor definierten speziellen funktionalen Anforderungen. Die Dokumentation gliedert sich in verschiedene patientenindividuell einzusetzende Module, die auf einem zuvor festgelegten Merkmalskatalog beruhen. Aufgrund spezieller funktionaler Anforderungen wurde eine eigene Datenerfassungsanwendung auf der Basis von ORACLE und ORACLE Forms entwickelt und implementiert. Die speziellen Anforderungen umfassten u.a. die Einbindung grafischer Stammbaumdarstellungen, den strukturierten Upload von Stammbaumdaten und molekulargenetischen Informationen, die automatisierte Altdatenubernahme aus dem Vorgangersystem, sowie die freie Programmierbarkeit von beliebig komplexen Datenbankabfragen zur zentralen Datenqualitatsprufung. In die Anwendung ist eine Datenbank zur patienten-unabhangigen Verwaltung genetischer Risikovarianten nahtlos integriert und mit den patientenbezogenen Daten verknupft. Die Vor- und Nachteile der gewahlten IT-Losung werden kritisch diskutiert. Insgesamt kommen wir zu der Schlussfolgerung, dass es angesichts der komplexen Dokumentation und der speziellen Funktionsanforderungen alternativ keine fertigen Softwareprodukte zu der von uns gewahlten Eigenentwicklung existieren. Abstract The national registry HerediCaRe for the evaluation and improvement of risk-adjusted prevention in hereditary breast and ovarian cancer is one of six model registries in health services research funded by the BMBF. In this paper, we describe and discuss the documentation and IT solution chosen for standardized data collection based on the specific functional requirements previously defined
Published: 2021

8. Breast cancer risk inBRCA1/2mutation carriers and noncarriers under prospective intensified surveillance

Author: Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, Schmutzler, Rita K., Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, and Schmutzler, Rita K.
Abstract: Comparably little is known about breast cancer (BC) risks in women from families tested negative forBRCA1/2mutations despite an indicative family history, as opposed toBRCA1/2mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers ofBRCA1/2mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n= 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n= 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) forBRCA1mutation carriers, 43.2% (95% CI 32.1-56.3%) forBRCA2mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) forBRCA1mutation carriers, 13.5 (95% CI 9.2-19.1) forBRCA2mutation carriers and 4.9 (95% CI 3.8-6.3) forBRCA1/2noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) forBRCA1mutation carriers, 6.6% (95% CI 3.4-12.5%) forBRCA2mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women fromBRCA1/2negative families with elevated risk.
Published: 2020

9. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

Author: Engel, Christoph, Ahadova, Aysel, Seppala, Toni T., Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, Blaeker, Hendrik, Bucksch, Karolin, Buettner, Reinhard, Cappel, Wouter T. De Vos Tot Nederveen, Endris, Volker, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Koornstra, Jan J., Langers, Alexandra M., Lepisto, Anna, Morak, Monika, Moeslein, Gabriela, Peltomaeki, Paivi, Pylvaenaeinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Schulmann, Karsten, Steinke-Lange, Verena, Stenzinger, Albrecht, Strassburg, Christian P., van de Meeberg, Paul C., van Kouwen, Mariette, van Leerdam, Monique, Vangala, Deepak B., Vecht, Juda, Verhulst, Marie-Louise, Doeberitz, Magnus von Knebel, Weitz, Juergen, Zachariae, Silke, Loeffler, Markus, Mecklin, Jukka-Pekka, Kloor, Matthias, Vasen, Hans F., Engel, Christoph, Ahadova, Aysel, Seppala, Toni T., Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, Blaeker, Hendrik, Bucksch, Karolin, Buettner, Reinhard, Cappel, Wouter T. De Vos Tot Nederveen, Endris, Volker, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Koornstra, Jan J., Langers, Alexandra M., Lepisto, Anna, Morak, Monika, Moeslein, Gabriela, Peltomaeki, Paivi, Pylvaenaeinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Schulmann, Karsten, Steinke-Lange, Verena, Stenzinger, Albrecht, Strassburg, Christian P., van de Meeberg, Paul C., van Kouwen, Mariette, van Leerdam, Monique, Vangala, Deepak B., Vecht, Juda, Verhulst, Marie-Louise, Doeberitz, Magnus von Knebel, Weitz, Juergen, Zachariae, Silke, Loeffler, Markus, Mecklin, Jukka-Pekka, Kloor, Matthias, and Vasen, Hans F.
Abstract: BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are
Published: 2020

10. Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study

Author: Bucksch, Karolin, Zachariae, Silke, Aretz, Stefan, Buettner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus von Knebel, Morak, Monika, Moeslein, Gabriela, Nattermann, Jacob, Perne, Claudia, Rahner, Nils, Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, Engel, Christoph, Bucksch, Karolin, Zachariae, Silke, Aretz, Stefan, Buettner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus von Knebel, Morak, Monika, Moeslein, Gabriela, Nattermann, Jacob, Perne, Claudia, Rahner, Nils, Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, and Engel, Christoph
Abstract: BackgroundIndividuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.MethodsData was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.ResultsThe number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS
Published: 2020

11. Breast cancer risk inBRCA1/2mutation carriers and noncarriers under prospective intensified surveillance

Author: Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, Schmutzler, Rita K., Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, and Schmutzler, Rita K.
Abstract: Comparably little is known about breast cancer (BC) risks in women from families tested negative forBRCA1/2mutations despite an indicative family history, as opposed toBRCA1/2mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers ofBRCA1/2mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n= 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n= 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) forBRCA1mutation carriers, 43.2% (95% CI 32.1-56.3%) forBRCA2mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) forBRCA1mutation carriers, 13.5 (95% CI 9.2-19.1) forBRCA2mutation carriers and 4.9 (95% CI 3.8-6.3) forBRCA1/2noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) forBRCA1mutation carriers, 6.6% (95% CI 3.4-12.5%) forBRCA2mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women fromBRCA1/2negative families with elevated risk.
Published: 2020

12. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

Author: Engel, Christoph, Ahadova, Aysel, Seppala, Toni T., Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, Blaeker, Hendrik, Bucksch, Karolin, Buettner, Reinhard, Cappel, Wouter T. De Vos Tot Nederveen, Endris, Volker, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Koornstra, Jan J., Langers, Alexandra M., Lepisto, Anna, Morak, Monika, Moeslein, Gabriela, Peltomaeki, Paivi, Pylvaenaeinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Schulmann, Karsten, Steinke-Lange, Verena, Stenzinger, Albrecht, Strassburg, Christian P., van de Meeberg, Paul C., van Kouwen, Mariette, van Leerdam, Monique, Vangala, Deepak B., Vecht, Juda, Verhulst, Marie-Louise, Doeberitz, Magnus von Knebel, Weitz, Juergen, Zachariae, Silke, Loeffler, Markus, Mecklin, Jukka-Pekka, Kloor, Matthias, Vasen, Hans F., Engel, Christoph, Ahadova, Aysel, Seppala, Toni T., Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, Blaeker, Hendrik, Bucksch, Karolin, Buettner, Reinhard, Cappel, Wouter T. De Vos Tot Nederveen, Endris, Volker, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Koornstra, Jan J., Langers, Alexandra M., Lepisto, Anna, Morak, Monika, Moeslein, Gabriela, Peltomaeki, Paivi, Pylvaenaeinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Schulmann, Karsten, Steinke-Lange, Verena, Stenzinger, Albrecht, Strassburg, Christian P., van de Meeberg, Paul C., van Kouwen, Mariette, van Leerdam, Monique, Vangala, Deepak B., Vecht, Juda, Verhulst, Marie-Louise, Doeberitz, Magnus von Knebel, Weitz, Juergen, Zachariae, Silke, Loeffler, Markus, Mecklin, Jukka-Pekka, Kloor, Matthias, and Vasen, Hans F.
Abstract: BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are
Published: 2020

13. Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study

Author: Bucksch, Karolin, Zachariae, Silke, Aretz, Stefan, Buettner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus von Knebel, Morak, Monika, Moeslein, Gabriela, Nattermann, Jacob, Perne, Claudia, Rahner, Nils, Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, Engel, Christoph, Bucksch, Karolin, Zachariae, Silke, Aretz, Stefan, Buettner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Kloor, Matthias, Doeberitz, Magnus von Knebel, Morak, Monika, Moeslein, Gabriela, Nattermann, Jacob, Perne, Claudia, Rahner, Nils, Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vangala, Deepak B., Weitz, Juergen, Loeffler, Markus, and Engel, Christoph
Abstract: BackgroundIndividuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.MethodsData was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.ResultsThe number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS
Published: 2020

14. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer

Author: Bick, Ulrich, Engel, Christoph, Krug, Barbara, Heindel, Walter, Fallenberg, Eva M., Rhiem, Kerstin, Maintz, David, Golatta, Michael, Speiser, Dorothee, Rjosk-Dendorfer, Dorothea, Laemmer-Skarke, Irina, Dietzel, Frederic, Schaefer, Karl Werner Fritz, Leinert, Elena, Weigel, Stefanie, Sauer, Stephanie, Pertschy, Stefanie, Hofmockel, Thomas, Hagert-Winkler, Anne, Kast, Karin, Quante, Anne, Meindl, Alfons, Kiechle, Marion, Loeffler, Markus, Schmutzler, Rita K., Blohmer, Jens-Uwe, Horn, Denise, Varon-Mateeva, Raymonda, Huebbel, Verena, Herold, Natalie, Puesken, Michael, Wimberger, Pauline, Meisel, Cornelia, Keller, Katja, Antoch, Gerald, Vesper, Anne-Sophie, Fehm, Tanja N., Schlegelberger, Brigitte, Auber, Bernd, Wallaschek, Hannah, Heil, Joerg, Schott, Sarah, Dikow, Nicola, Mundhenke, Christoph, Arnold, Norbert, Caliebe, Almuth, Briest, Susanne, Lemke, Johannes, Gril, Sabine, Pfeifer, Katharina, Ramser, Juliane, Mahner, Sven, Ditsch, Nina, Zeder-Goess, Christine, Tio, Joke, Burg, Matthias, Horvath, Judith, Siebert, Reiner, Bartholomae, Jasmin, Janni, Wolfgang, Bley, Thorsten, Woeckel, Achim, Haaf, Thomas, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Bick, Ulrich, Engel, Christoph, Krug, Barbara, Heindel, Walter, Fallenberg, Eva M., Rhiem, Kerstin, Maintz, David, Golatta, Michael, Speiser, Dorothee, Rjosk-Dendorfer, Dorothea, Laemmer-Skarke, Irina, Dietzel, Frederic, Schaefer, Karl Werner Fritz, Leinert, Elena, Weigel, Stefanie, Sauer, Stephanie, Pertschy, Stefanie, Hofmockel, Thomas, Hagert-Winkler, Anne, Kast, Karin, Quante, Anne, Meindl, Alfons, Kiechle, Marion, Loeffler, Markus, Schmutzler, Rita K., Blohmer, Jens-Uwe, Horn, Denise, Varon-Mateeva, Raymonda, Huebbel, Verena, Herold, Natalie, Puesken, Michael, Wimberger, Pauline, Meisel, Cornelia, Keller, Katja, Antoch, Gerald, Vesper, Anne-Sophie, Fehm, Tanja N., Schlegelberger, Brigitte, Auber, Bernd, Wallaschek, Hannah, Heil, Joerg, Schott, Sarah, Dikow, Nicola, Mundhenke, Christoph, Arnold, Norbert, Caliebe, Almuth, Briest, Susanne, Lemke, Johannes, Gril, Sabine, Pfeifer, Katharina, Ramser, Juliane, Mahner, Sven, Ditsch, Nina, Zeder-Goess, Christine, Tio, Joke, Burg, Matthias, Horvath, Judith, Siebert, Reiner, Bartholomae, Jasmin, Janni, Wolfgang, Bley, Thorsten, Woeckel, Achim, Haaf, Thomas, Zachariae, Silke, Bucksch, Karolin, and Enders, Ute
Abstract: Purpose To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. Results A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5 (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9 parts per thousand (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. Conclusions High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.
Published: 2019

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

Author: Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., Spurdle, Amanda B., Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., and Spurdle, Amanda B.
Abstract: 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.
Published: 2019

16. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer

Author: Bick, Ulrich, Engel, Christoph, Krug, Barbara, Heindel, Walter, Fallenberg, Eva M., Rhiem, Kerstin, Maintz, David, Golatta, Michael, Speiser, Dorothee, Rjosk-Dendorfer, Dorothea, Laemmer-Skarke, Irina, Dietzel, Frederic, Schaefer, Karl Werner Fritz, Leinert, Elena, Weigel, Stefanie, Sauer, Stephanie, Pertschy, Stefanie, Hofmockel, Thomas, Hagert-Winkler, Anne, Kast, Karin, Quante, Anne, Meindl, Alfons, Kiechle, Marion, Loeffler, Markus, Schmutzler, Rita K., Blohmer, Jens-Uwe, Horn, Denise, Varon-Mateeva, Raymonda, Huebbel, Verena, Herold, Natalie, Puesken, Michael, Wimberger, Pauline, Meisel, Cornelia, Keller, Katja, Antoch, Gerald, Vesper, Anne-Sophie, Fehm, Tanja N., Schlegelberger, Brigitte, Auber, Bernd, Wallaschek, Hannah, Heil, Joerg, Schott, Sarah, Dikow, Nicola, Mundhenke, Christoph, Arnold, Norbert, Caliebe, Almuth, Briest, Susanne, Lemke, Johannes, Gril, Sabine, Pfeifer, Katharina, Ramser, Juliane, Mahner, Sven, Ditsch, Nina, Zeder-Goess, Christine, Tio, Joke, Burg, Matthias, Horvath, Judith, Siebert, Reiner, Bartholomae, Jasmin, Janni, Wolfgang, Bley, Thorsten, Woeckel, Achim, Haaf, Thomas, Zachariae, Silke, Bucksch, Karolin, Enders, Ute, Bick, Ulrich, Engel, Christoph, Krug, Barbara, Heindel, Walter, Fallenberg, Eva M., Rhiem, Kerstin, Maintz, David, Golatta, Michael, Speiser, Dorothee, Rjosk-Dendorfer, Dorothea, Laemmer-Skarke, Irina, Dietzel, Frederic, Schaefer, Karl Werner Fritz, Leinert, Elena, Weigel, Stefanie, Sauer, Stephanie, Pertschy, Stefanie, Hofmockel, Thomas, Hagert-Winkler, Anne, Kast, Karin, Quante, Anne, Meindl, Alfons, Kiechle, Marion, Loeffler, Markus, Schmutzler, Rita K., Blohmer, Jens-Uwe, Horn, Denise, Varon-Mateeva, Raymonda, Huebbel, Verena, Herold, Natalie, Puesken, Michael, Wimberger, Pauline, Meisel, Cornelia, Keller, Katja, Antoch, Gerald, Vesper, Anne-Sophie, Fehm, Tanja N., Schlegelberger, Brigitte, Auber, Bernd, Wallaschek, Hannah, Heil, Joerg, Schott, Sarah, Dikow, Nicola, Mundhenke, Christoph, Arnold, Norbert, Caliebe, Almuth, Briest, Susanne, Lemke, Johannes, Gril, Sabine, Pfeifer, Katharina, Ramser, Juliane, Mahner, Sven, Ditsch, Nina, Zeder-Goess, Christine, Tio, Joke, Burg, Matthias, Horvath, Judith, Siebert, Reiner, Bartholomae, Jasmin, Janni, Wolfgang, Bley, Thorsten, Woeckel, Achim, Haaf, Thomas, Zachariae, Silke, Bucksch, Karolin, and Enders, Ute
Abstract: Purpose To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. Results A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5 (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9 parts per thousand (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. Conclusions High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.
Published: 2019

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

Author: Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., Spurdle, Amanda B., Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., and Spurdle, Amanda B.
Abstract: 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.
Published: 2019

18. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Author: Engel, Christoph, Rhiem, Kerstin, Hahnen, Eric, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Bluemcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Riess, Olaf, Emons, Guenter, Weber, Bernhard H. F., Engel, Jutta, Schmutzler, Rita K., Engel, Christoph, Rhiem, Kerstin, Hahnen, Eric, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Bluemcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Riess, Olaf, Emons, Guenter, Weber, Bernhard H. F., Engel, Jutta, and Schmutzler, Rita K.
Abstract: Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Published: 2018

19. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

Author: Engel, Christoph, Vasen, Hans F., Seppala, Toni, Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, de Boer, Sybrand Y., Bucksch, Karolin, Buttner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Jarvinen, Heikki, Kloor, Matthias, Doeberitz, Magnus von Knebel, Koornstra, Jan J., van Kouwen, Mariette, Langers, Alexandra M., van de Meeberg, Paul C., Morak, Monika, Moeslein, Gabriela, Nagengast, Fokko M., Pylvanainen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Sanduleanu, Silvia, Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vecht, Juda, Verhulst, Marie-Louise, Cappel, Wouter de Vos Tot Nederveen, Zachariae, Silke, Mecklin, Jukka-Pekka, Loeffler, Markus, Engel, Christoph, Vasen, Hans F., Seppala, Toni, Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, de Boer, Sybrand Y., Bucksch, Karolin, Buttner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Jarvinen, Heikki, Kloor, Matthias, Doeberitz, Magnus von Knebel, Koornstra, Jan J., van Kouwen, Mariette, Langers, Alexandra M., van de Meeberg, Paul C., Morak, Monika, Moeslein, Gabriela, Nagengast, Fokko M., Pylvanainen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Sanduleanu, Silvia, Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vecht, Juda, Verhulst, Marie-Louise, Cappel, Wouter de Vos Tot Nederveen, Zachariae, Silke, Mecklin, Jukka-Pekka, and Loeffler, Markus
Abstract: BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low-and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and [GRAPHICS] time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance interval
Published: 2018

20. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Author: Engel, Christoph, Rhiem, Kerstin, Hahnen, Eric, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Bluemcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Riess, Olaf, Emons, Guenter, Weber, Bernhard H. F., Engel, Jutta, Schmutzler, Rita K., Engel, Christoph, Rhiem, Kerstin, Hahnen, Eric, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Bluemcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Riess, Olaf, Emons, Guenter, Weber, Bernhard H. F., Engel, Jutta, and Schmutzler, Rita K.
Abstract: Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Published: 2018

21. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

Author: Engel, Christoph, Vasen, Hans F., Seppala, Toni, Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, de Boer, Sybrand Y., Bucksch, Karolin, Buttner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Jarvinen, Heikki, Kloor, Matthias, Doeberitz, Magnus von Knebel, Koornstra, Jan J., van Kouwen, Mariette, Langers, Alexandra M., van de Meeberg, Paul C., Morak, Monika, Moeslein, Gabriela, Nagengast, Fokko M., Pylvanainen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Sanduleanu, Silvia, Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vecht, Juda, Verhulst, Marie-Louise, Cappel, Wouter de Vos Tot Nederveen, Zachariae, Silke, Mecklin, Jukka-Pekka, Loeffler, Markus, Engel, Christoph, Vasen, Hans F., Seppala, Toni, Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, de Boer, Sybrand Y., Bucksch, Karolin, Buttner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Jarvinen, Heikki, Kloor, Matthias, Doeberitz, Magnus von Knebel, Koornstra, Jan J., van Kouwen, Mariette, Langers, Alexandra M., van de Meeberg, Paul C., Morak, Monika, Moeslein, Gabriela, Nagengast, Fokko M., Pylvanainen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Sanduleanu, Silvia, Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vecht, Juda, Verhulst, Marie-Louise, Cappel, Wouter de Vos Tot Nederveen, Zachariae, Silke, Mecklin, Jukka-Pekka, and Loeffler, Markus
Abstract: BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low-and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and [GRAPHICS] time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance interval
Published: 2018

22. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Author: German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), Engel, Christoph, Rhiem, Kerstin E. M., Hahnen, Eric Thomas, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Blümcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Rieß, Olaf, Emons, Günter, Weber, Bernhard H. F., Engel, Jutta, Schmutzler, Rita Katharina, German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), Engel, Christoph, Rhiem, Kerstin E. M., Hahnen, Eric Thomas, Loibl, Sibylle, Weber, Karsten E., Seiler, Sabine, Zachariae, Silke, Hauke, Jan, Wappenschmidt, Barbara, Waha, Anke, Blümcke, Britta, Kiechle, Marion, Meindl, Alfons, Niederacher, Dieter, Bartram, Claus R., Speiser, Dorothee, Schlegelberger, Brigitte, Arnold, Norbert, Wieacker, Peter, Leinert, Elena, Gehrig, Andrea, Briest, Susanne, Kast, Karin, Rieß, Olaf, Emons, Günter, Weber, Bernhard H. F., Engel, Jutta, and Schmutzler, Rita Katharina
Abstract: Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Published: 2018

23. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

Author: Kast, Karin, Rhiem, Kerstin, Wappenschmidt, Barbara, Hahnen, Eric, Hauke, Jan, Bluemcke, Britta, Zarghooni, Verena, Herold, Natalie, Ditsch, Nina, Kiechle, Marion, Braun, Michael, Fischer, Christine, Dikow, Nicola, Schott, Sarah, Rahner, Nils, Niederacher, Dieter, Fehm, Tanja, Gehrig, Andrea, Mueller-Reible, Clemens, Arnold, Norbert, Maass, Nicolai, Borck, Guntram, de Gregorio, Nikolaus, Scholz, Caroline, Auber, Bernd, Varon-Manteeva, Raymonda, Speiser, Dorothee, Horvath, Judit, Lichey, Nadine, Wimberger, Pauline, Stark, Sylvia, Faust, Ulrike, Weber, Bernhard H. F., Emons, Gunter, Zachariae, Silke, Meindl, Alfons, Schmutzler, Rita K., Engel, Christoph, Kast, Karin, Rhiem, Kerstin, Wappenschmidt, Barbara, Hahnen, Eric, Hauke, Jan, Bluemcke, Britta, Zarghooni, Verena, Herold, Natalie, Ditsch, Nina, Kiechle, Marion, Braun, Michael, Fischer, Christine, Dikow, Nicola, Schott, Sarah, Rahner, Nils, Niederacher, Dieter, Fehm, Tanja, Gehrig, Andrea, Mueller-Reible, Clemens, Arnold, Norbert, Maass, Nicolai, Borck, Guntram, de Gregorio, Nikolaus, Scholz, Caroline, Auber, Bernd, Varon-Manteeva, Raymonda, Speiser, Dorothee, Horvath, Judit, Lichey, Nadine, Wimberger, Pauline, Stark, Sylvia, Faust, Ulrike, Weber, Bernhard H. F., Emons, Gunter, Zachariae, Silke, Meindl, Alfons, Schmutzler, Rita K., and Engel, Christoph
Abstract: Purpose To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. Patients and methods Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. Results The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). Conclusions Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.
Published: 2016

24. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

Author: Kast, Karin, Rhiem, Kerstin, Wappenschmidt, Barbara, Hahnen, Eric, Hauke, Jan, Bluemcke, Britta, Zarghooni, Verena, Herold, Natalie, Ditsch, Nina, Kiechle, Marion, Braun, Michael, Fischer, Christine, Dikow, Nicola, Schott, Sarah, Rahner, Nils, Niederacher, Dieter, Fehm, Tanja, Gehrig, Andrea, Mueller-Reible, Clemens, Arnold, Norbert, Maass, Nicolai, Borck, Guntram, de Gregorio, Nikolaus, Scholz, Caroline, Auber, Bernd, Varon-Manteeva, Raymonda, Speiser, Dorothee, Horvath, Judit, Lichey, Nadine, Wimberger, Pauline, Stark, Sylvia, Faust, Ulrike, Weber, Bernhard H. F., Emons, Gunter, Zachariae, Silke, Meindl, Alfons, Schmutzler, Rita K., Engel, Christoph, Kast, Karin, Rhiem, Kerstin, Wappenschmidt, Barbara, Hahnen, Eric, Hauke, Jan, Bluemcke, Britta, Zarghooni, Verena, Herold, Natalie, Ditsch, Nina, Kiechle, Marion, Braun, Michael, Fischer, Christine, Dikow, Nicola, Schott, Sarah, Rahner, Nils, Niederacher, Dieter, Fehm, Tanja, Gehrig, Andrea, Mueller-Reible, Clemens, Arnold, Norbert, Maass, Nicolai, Borck, Guntram, de Gregorio, Nikolaus, Scholz, Caroline, Auber, Bernd, Varon-Manteeva, Raymonda, Speiser, Dorothee, Horvath, Judit, Lichey, Nadine, Wimberger, Pauline, Stark, Sylvia, Faust, Ulrike, Weber, Bernhard H. F., Emons, Gunter, Zachariae, Silke, Meindl, Alfons, Schmutzler, Rita K., and Engel, Christoph
Abstract: Purpose To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. Patients and methods Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. Results The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). Conclusions Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.
Published: 2016

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24 results on '"Zachariae, Silke"'

1. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

2. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

3. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

4. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

5. Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X

6. HerediCaRe: Documentation and IT Solution of a Specialized Registry for Hereditary Breast and Ovarian Cancer

7. HerediCaRe: Documentation and IT Solution of a Specialized Registry for Hereditary Breast and Ovarian Cancer

8. Breast cancer risk inBRCA1/2mutation carriers and noncarriers under prospective intensified surveillance

9. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

10. Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study

11. Breast cancer risk inBRCA1/2mutation carriers and noncarriers under prospective intensified surveillance

12. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

13. Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study

14. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer

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

16. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer

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

18. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

19. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

20. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

21. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

22. Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

23. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

24. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

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24 results on '"Zachariae, Silke"'

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