ArticleBreast cancer research : BCR2020
Tumor sequencing is useful to refine the analysis of germline variants in unexplained high-risk breast cancer families.
Article in Breast cancer research : BCR, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 22 citations in OpenAlex.
- A comprehensive genomic framework for identifying genes predisposing to homologous recombination repair-deficient breast or ovarian cancer.BJC reports · 2026Article
- Molecular Basis of Adenomatous Gastrointestinal Polyposis Syndromes: Role of Pathogenic and Benign Variants in Disease Onset.Biomedicines · 2026Article
- Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing.NPJ genomic medicine · 2025Article
- Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness.Breast cancer research : BCR · 2023Article
- Genomic Landscape of Normal and Breast Cancer Tissues in a Hungarian Pilot Cohort.International journal of molecular sciences · 2023Article
- An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.Frontiers in oncology · 2022Article
- Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) CellsDisease markers · 2021Article
- Application Areas of Traditional Molecular Genetic Methods and NGS in relation to Hereditary Urological Cancer Diagnosis.Journal of oncology · 2020Review
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Authors and funding
19 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundMultigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene.
methodsWhole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate.
resultsSixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation.
conclusionTumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.
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