Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility
Keupp, Katharina (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Hampp, Stephanie (Department of Obstetrics and Gynecology. Ulm University)
Hübbel, Annette (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Maringa, Monika (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Kostezka, Sarah (Department of Obstetrics and Gynecology. Ulm University)
Rhiem, Kerstin (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Waha, Anke (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Wappenschmidt, Barbara (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Pujol, Roser. (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Surrallés i Calonge, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Schmutzler, Rita K. (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)
Wiesmüller, Lisa (Department of Obstetrics and Gynecology. Ulm University)
Hahnen, Eric (Center for Familial Breast and Ovarian Cancer. Center for Integrated Oncology (CIO). University of Cologne)

Date:	2019
Abstract:	Background: Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. We report biallelic BRCA1 mutations c. 181T > G (p. Cys61Gly) and c. 5096G > A (p. Arg1699Gln) in a woman with breast cancer diagnosed at the age of 30 years. The common European founder mutation p. Cys61Gly confers high cancer risk, whereas the deleterious p. Arg1699Gln is hypomorphic and was suggested to confer intermediate cancer risk. Methods and Results: Aside from significant toxicity from chemotherapy, the patient showed mild FA-like features (e. g. , short stature, microcephaly, skin hyperpigmentation). Chromosome fragility, a hallmark of FA patient cells, was not present in patient-derived peripheral blood lymphocytes. We demonstrated that the p. Arg1699Gln mutation impairs DNA double-strand break repair, elevates RAD51 foci levels at baseline, and compromises BRCA1 protein function in protecting from replication stress. Although the p. Arg1699Gln mutation compromises BRCA1 function, the residual activity of the p. Arg1699Gln allele likely prevents from chromosome fragility and a more severe FA phenotype. Conclusion: Our data expand the clinical spectrum associated with biallelic BRCA1 mutations, ranging from embryonic lethality to a mild FA-like phenotype and no chromosome fragility.
Grants:	Ministerio de Economía y Competitividad SAF2015-64152-R
Note:	Altres ajuts: Deutsche Krebshilfe, Grant/Award Number: 110837, 70111850 and 70112504
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Biallelic BRCA1 ; Early onset breast cancer ; Fanconi anemia ; P.arg1699gln
Published in:	Molecular genetics & genomic medicine, Vol. 7 Núm. 9 (january 2019) , p. e863, ISSN 2324-9269

DOI: 10.1002/mgg3.863
PMID: 31347298

9 p, 821.2 KB

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