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Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients.
van der Merwe, Nerina C; Buccimazza, Ines; Rossouw, Bianca; Araujo, Monica; Ntaita, Kholiwe S; Schoeman, Mardelle; Vorster, Karin; Napo, Kgabo; Kotze, Maritha J; Oosthuizen, Jaco.
Afiliación
  • van der Merwe NC; Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa. vanderMerweNC@ufs.ac.za.
  • Buccimazza I; Division of Human Genetics, National Health Laboratory Service, Universitas Hospital, Bloemfontein, South Africa. vanderMerweNC@ufs.ac.za.
  • Rossouw B; Genetics Unit, Inkosi Albert Luthuli General Hospital, Durban, South Africa.
  • Araujo M; Department of Surgery, Nelson R Mandela School of Medicine, Inkosi Albert Luthuli General Hospital, Durban, South Africa.
  • Ntaita KS; Division of Human Genetics, National Health Laboratory Service, Braamfontein, Johannesburg, South Africa.
  • Schoeman M; Division of Human Genetics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • Vorster K; Division of Human Genetics, National Health Laboratory Service, Braamfontein, Johannesburg, South Africa.
  • Napo K; Division of Human Genetics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • Kotze MJ; Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
  • Oosthuizen J; Division of Human Genetics, National Health Laboratory Service, Universitas Hospital, Bloemfontein, South Africa.
Breast Cancer Res Treat ; 207(2): 331-342, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38814507
ABSTRACT

PURPOSE:

Genetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa.

METHODS:

DNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications.

RESULTS:

Six of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case.

CONCLUSION:

This study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteína BRCA1 / Predisposición Genética a la Enfermedad / Proteína BRCA2 / Secuenciación de Nucleótidos de Alto Rendimiento / Reparación del ADN por Recombinación / Heterocigoto Límite: Adult / Aged / Female / Humans / Middle aged País/Región como asunto: Africa Idioma: En Revista: Breast Cancer Res Treat Año: 2024 Tipo del documento: Article País de afiliación: Sudáfrica Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteína BRCA1 / Predisposición Genética a la Enfermedad / Proteína BRCA2 / Secuenciación de Nucleótidos de Alto Rendimiento / Reparación del ADN por Recombinación / Heterocigoto Límite: Adult / Aged / Female / Humans / Middle aged País/Región como asunto: Africa Idioma: En Revista: Breast Cancer Res Treat Año: 2024 Tipo del documento: Article País de afiliación: Sudáfrica Pais de publicación: Países Bajos