Molecular Trajectory of BRCA1 and BRCA2 Mutations

Hatano, Yuichiro; Tamada, Maho; Matsuo, Mikiko; Hara, Akira

doi:10.3389/fonc.2020.00361

“…continued) BRCA2 are Fanconi anemia-like genes,37 encoding proteins important for DNA repair pathways active in the BM. Individuals with BRCA pathway mutations are at increased risk for the development of hematopoietic malignancies 38.…”

mentioning

confidence: 99%

Identifying potential germline variants from sequencing hematopoietic malignancies

Kraft

¹

,

Godley

²

2020

View full text Add to dashboard Cite

Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.

show abstract

“…It should be noted that in the study design we included both women with sporadic BC as well as women with family history of ovarian and/or breast cancers in order to evaluate if the methylation status of the studied genes could be a differentiation factor since mutations or methylation of BRCA1/BRCA2 do not account for all cases of familial BC 52‐54 . On the other hand, approximately a quarter to half of ovarian cancers with germline BRCA1 / BRCA2 mutations was reported to reverse the inherited mutation suggesting that in vivo retrieval of BRCA function is a potent oncogenic event to resist unwanted DNA damage and therefore other genetic factors may contribute to disease pathogenesis and progression 55‐57 …”

Section: Methodsmentioning

confidence: 99%

DNA methylation patterns of RAR‐β2 and RASSF1A gene promoters in FNAB samples from Greek population with benign or malignant breast lesions

Kougioumtsidou

¹

,

Vavoulidis

²

,

Nasioutziki

³

et al. 2020

Diagnostic Cytopathology

1

0

View full text Add to dashboard Cite

Background Promoter hypermethylation is common in Breast Cancer (BC) with studies mainly in histological specimens showing frequent methylation of tumor suppressor genes (TSGs) compared with normal tissues. The aim of this study was to estimate the frequency of promoter methylation of RAR‐β2 and RASSF1A genes in breast FNAB material aiming to evaluate the methylation status of these two genes as biomarker for detecting BC in Greek population. Methods FNAB material from 104 patients was collected for cytological evaluation and epigenetic analysis. DNA was extracted and subjected to bisulfite conversion. A methylation‐specific PCR was carried out and the final products were separated with electrophoresis in 2% agarose gels. Results From 104 samples, RASSF1A hypermethylation was observed in 78 (75%) and RAR‐β2 hypermethylation in 64 (61.6%). 84% and 78% of the cases diagnosed with breast malignancy (n = 50) were methylated for RASSF1A and RAR‐β2, respectively. Methylated RASSF1A and RAR‐β2 were also detected in 88.3% and 76.5% in samples diagnosed as suspicious for malignancy (n = 17) and in 57.2% of samples diagnosed with atypia (n = 14). The Odds Ratio for breast malignancy was 4.545 in patients with RASSF1A hypermethylation and 9.167 in patients with RAR‐β2 hypermethylation underlying their promoter's methylation positive correlation with breast malignancy. Conclusion To optimize the sensitivity and specificity of this epigenetic setting, more TSGs related to BC should be gradually imported in our evaluated methylation panel and be validated in a larger study sample with the aim that the obtained epigenetic profiles will provide clinicians with valuable tools for management of BC patients in Greece.

show abstract

“…Genetic counseling and testing were warranted at the time of his first cancer based on his extensive family cancer history. (2) BRCA1 and BRCA2 are Fanconi anemia-like genes, 37 encoding proteins important for DNA repair pathways active in the BM. Individuals with BRCA pathway mutations are at increased risk for the development of hematopoietic malignancies.…”

Section: Identifying Potential Germline Alterationsmentioning

confidence: 99%

Identifying potential germline variants from sequencing hematopoietic malignancies

Kraft

¹

,

Godley

²

2020

Blood

View full text Add to dashboard Cite

Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.

show abstract

Molecular Trajectory of BRCA1 and BRCA2 Mutations

Cited by 38 publications

References 118 publications

Identifying potential germline variants from sequencing hematopoietic malignancies

Identifying potential germline variants from sequencing hematopoietic malignancies

DNA methylation patterns of RAR‐β2 and RASSF1A gene promoters in FNAB samples from Greek population with benign or malignant breast lesions

Identifying potential germline variants from sequencing hematopoietic malignancies

Contact Info

Product

Resources

About