Complex Characterization of Germline Large Genomic Rearrangements of the BRCA1 and BRCA2 Genes in High-Risk Breast Cancer Patients—Novel Variants from a Large National Center

Bozsik, Anikó; Pócza, Tímea; Papp, J.; Tibor, Vaszko; Butz, Henriett; Patócs, Attila; Oláh, Edit

doi:10.3390/ijms21134650

Cited by 17 publications

(21 citation statements)

References 48 publications

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“…Genetic analyses were done as we previously reported [ 62 ]. Germline BRCA1/2 variant status was evaluated following library preparation using CE-IVD BRCA MASTR Plus Dx kit (Agilent, Santa Clara, CA, United States).…”

Section: Methodsmentioning

confidence: 99%

Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Butz

Papp

Bozsik

et al. 2021

Cancers

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The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic BRCA1 or BRCA2 carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding BRCA2 C-terminal variants, no linkage with other pathogenic BRCA2 variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort.

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Section: Methodsmentioning

confidence: 99%

Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Butz

Papp

Bozsik

et al. 2021

Cancers

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“…(B) LRG_292t1:c.5213_5278-2753delinsA. Running name: BRCA1 del(ex20)insA (Belogianni et al, 2004;Bozsik et al, 2020). DNA stretch between the two double-strand breaks is deleted and the two exposed ends are rejoined by NHEJ without homology requirement.…”

Section: Svs -Underlying Causative Molecular Mechanismsmentioning

confidence: 99%

“…(C) LRG_292t1:c.442-1102_547+252del. Running name: BRCA1 del(ex8) (Bozsik et al, 2020). DNA ends are processed at the site of the double-strand break: 5 strands are resected by exonucleases (marked with scissors).…”

Section: Svs -Underlying Causative Molecular Mechanismsmentioning

confidence: 99%

“…(D) LRG_292t1:c.5278-492_5407-128delins236. Running name: BRCA1 del(ex21-22)ins236 (Zikan et al, 2008;Bozsik et al, 2020). Replication forks stalls at structural hindrance caused by palindrome sequence.…”

Section: Svs -Underlying Causative Molecular Mechanismsmentioning

confidence: 99%

“…The size of germline deletions affecting cancer-predisposing genes ranges from few hundreds of base pairs to several kilobases (Bozsik et al, 2020). Chromosome regions characterized by abundant directly oriented repeats, especially Alu sequences, are markedly prone to deletions primarily through the MMEJ mechanism (Smith et al, 2016).…”

Section: Examples Of Svs In Cancer-predisposing Genesmentioning

confidence: 99%

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Germline Structural Variations in Cancer Predisposition Genes

et al. 2021

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In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

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Comprehensive profiling of pathogenic germline large genomic rearrangements in a pan‐cancer analysis

Sun

Bai

Su³

et al. 2023

Molecular Oncology

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The presence of large genomic rearrangements (LGRs) has been heavily investigated in breast and ovarian cancer. However, correlations between LGRs and cancer types beyond these two have not been extensively profiled, likely due to the highly inefficient methods of detecting these types of alterations. This study utilized next‐generation sequencing (NGS) to analyze and classify the germline LGR profile in 17 025 cancer patients across 22 cancer types. We characterized newly identified LGRs based on predicted pathogenicity and took a closer look at genes that acquire both germline and somatic mutations within our samples. The detection method for LGRs was validated using droplet digital polymerase chain reaction (ddPCR) assay of commonly investigated LGR genes. In total, 15 659 samples from across 22 cancer types were retained for analysis after filtering. We observed that, in our cohort, the cancer types with the highest proportion of germline LGRs were ovarian cancer (4.7%), renal cell carcinoma (2.5%), breast cancer (2%), glioma (1.8%) and thyroid carcinoma (1.8%). Annotation of detected germline variants revealed several genes—MSH2, FANCA and PMS2—that contain novel LGRs. We observed co‐occurrences between germline LGRs in MSH2 and somatic single nucleotide variants/insertion and deletions (SNVs/InDels) in BRCA2, KTM2B, KDM5A, CHD8, and HNF1A. Furthermore, our analysis showed that samples with pathogenic and likely pathogenic germline LGRs tended to also have higher mutational burden, chromosomal instability, and microsatellite instability ratio compared to samples with pathogenic germline SNVs/InDels. In this study, we demonstrated the prevalence of pathogenic germline LGRs beyond breast and ovarian cancer. The profiles of these pathogenic or likely pathogenic alterations will fuel further investigations and highlight new understanding of LGRs across multiple cancer types.

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Complex Characterization of Germline Large Genomic Rearrangements of the BRCA1 and BRCA2 Genes in High-Risk Breast Cancer Patients—Novel Variants from a Large National Center

Cited by 17 publications

References 48 publications

Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants

Germline Structural Variations in Cancer Predisposition Genes

Comprehensive profiling of pathogenic germline large genomic rearrangements in a pan‐cancer analysis

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